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Timothy Cloughesy M.D.

The Ronald Reagan Hospital at
UCLA Medical Center
710 Westwood Plaza
Reed Bldg RM 1-230
Los Angeles CA 90095

• Director, UCLA Neuro-Oncology
• Clinical Professor

Neurology, UCLA School of Medicine, 1993 - 2017

Medical Board Certification:
Neurology, American Board of Psychiatry and Neurology, 1993 - 2017

Neurological Oncology, Memorial Sloan-Kettering Cancer Center, 1991 - 1992

Neurology, UCLA School of Medicine, 1988 - 1991

Neurology, Maricopa Medical Center, 1987 - 1988

Medical Degree:
M.D., Tulane University School of Medicine, 1987

Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas.
Source:Journal of neuro-oncology
Authors:Nayak L; de Groot J; Wefel JS; Cloughesy TF; Lieberman F; Chang SM; Omuro A; Drappatz J; Batchelor TT; DeAngelis LM; Gilbert MR; Aldape KD; Yung AW; Fisher J; Ye X; Chen A; Grossman S; Prados M; Wen PY;
Abstract:Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks.
Incidence, survival, pathology, and genetics of adult Latino Americans with glioblastoma.
Source:Journal of neuro-oncology
Authors:Shabihkhani M; Telesca D; Movassaghi M; Naeini YB; Naeini KM; Hojat SA; Gupta D; Lucey GM; Ontiveros M; Wang MW; Hanna LS; Sanchez DE; Mareninov S; Khanlou N; Vinters HV; Bergsneider M; Nghiemphu PL; Lai A; Liau LM; Cloughesy TF; Yong WH;
Abstract:Latinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations. Latinos have a higher incidence of giant cell glioblastoma than non-Latino Whites while the incidence of gliosarcoma is similar. Despite lower rates of radiation therapy and greater rates of sub-total resection than non-Latino Whites, Latinos have better 1 and 5 year survival rates. SEER does not record chemotherapy data. Survivals of Latino sub-populations are similar with each other. Age, extent of resection, and the use of radiation therapy are associated with improved survival but none of these variables are sufficient in a multivariate analysis to explain the improved survival of Latinos relative to non-Latino Whites. As molecular data is not available in SEER records, we studied the MGMT and IDH status of 571 patients from a UCLA database. MGMT methylation and IDH1 mutation rates are not statistically significantly different between non-Latino Whites and Latinos. For UCLA patients with available information, chemotherapy and radiation rates are similar for non-Latino White and Latino patients, but the latter have lower rates of gross total resection and present at a younger age.
Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma.
Authors:Antonios JP; Soto H; Everson RG; Moughon D; Orpilla JR; Shin NP; Sedighim S; Treger J; Odesa S; Tucker A; Yong WH; Li G; Cloughesy TF; Liau LM; Prins RM;
Abstract:Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.
Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials.
Source:Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
Authors:Ellingson BM; Wen PY; Cloughesy TF;
Abstract:Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to overcome many of the challenges identified with previous guidelines for response assessment, however, significant challenges and limitations remain. The current recommendations build on the strengths of the current RANO criteria, while addressing many of these limitations. Modifications to the current RANO criteria include suggestions for volumetric response evaluation, use contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for newly diagnosed glioblastoma response assessment, and "treatment-agnostic" response assessment rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials.
Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Sulman EP; Ismaila N; Armstrong TS; Tsien C; Batchelor TT; Cloughesy T; Galanis E; Gilbert M; Gondi V; Lovely M; Mehta M; Mumber MP; Sloan A; Chang SM;
Abstract:Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy for glioblastoma. Because of its relevance to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies used to critically examine guidelines developed by other organizations. Methods The ASTRO guideline on radiation therapy for glioblastoma was reviewed for developmental rigor by methodologists. An ASCO endorsement panel updated the literature search and reviewed the content and recommendations. Results The ASCO endorsement panel determined that the recommendations from the ASTRO guideline, published in 2016, are clear, thorough, and based on current scientific evidence. ASCO endorsed the ASTRO guideline on radiation therapy for glioblastoma and added qualifying statements. Recommendations Partial-brain fractionated radiotherapy with concurrent and adjuvant temozolomide is the standard of care after biopsy or resection of newly diagnosed glioblastoma in patients up to 70 years of age. Hypofractionated radiotherapy for elderly patients with fair to good performance status is appropriate. The addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality of life for elderly patients with good performance status. Reasonable options for patients with poor performance status include hypofractionated radiotherapy alone, temozolomide alone, or best supportive care. Focal reirradiation represents an option for select patients with recurrent glioblastoma, although this is not supported by prospective randomized evidence. Additional information is available at and .
Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Onartuzumab Plus Bevacizumab Versus Placebo Plus Bevacizumab in Patients With Recurrent Glioblastoma: Efficacy, Safety, and Hepatocyte Growth Factor and O(6)-Methylguanine-DNA Methyltransferase Biomarker Analyses.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Cloughesy T; Finocchiaro G; Belda-Iniesta C; Recht L; Brandes AA; Pineda E; Mikkelsen T; Chinot OL; Balana C; Macdonald DR; Westphal M; Hopkins K; Weller M; Bais C; Sandmann T; Bruey JM; Koeppen H; Liu B; Verret W; Phan SC; Shames DS;
Abstract:Purpose Bevacizumab regimens are approved for the treatment of recurrent glioblastoma in many countries. Aberrant mesenchymal-epithelial transition factor (MET) expression has been reported in glioblastoma and may contribute to bevacizumab resistance. The phase II study GO27819 investigated the monovalent MET inhibitor onartuzumab plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pla + Bev) in recurrent glioblastoma. Methods At first recurrence after chemoradiation, bevacizumab-naïve patients with glioblastoma were randomly assigned 1:1 to receive Ona (15 mg/kg, once every 3 weeks) + Bev (15 mg/kg, once every 3 weeks) or Pla + Bev until disease progression. The primary end point was progression-free survival by response assessment in neuro-oncology criteria. Secondary end points were overall survival, objective response rate, duration of response, and safety. Exploratory biomarker analyses correlated efficacy with expression levels of MET ligand hepatocyte growth factor, O(6)-methylguanine-DNA methyltransferase promoter methylation, and glioblastoma subtype. Results Among 129 patients enrolled (Ona + Bev, n = 64; Pla + Bev, n = 65), baseline characteristics were balanced. The median progression-free survival was 3.9 months for Ona + Bev versus 2.9 months for Pla + Bev (hazard ratio, 1.06; 95% CI, 0.72 to 1.56; P = .7444). The median overall survival was 8.8 months for Ona + Bev and 12.6 months for Pla + Bev (hazard ratio, 1.45; 95% CI, 0.88 to 2.37; P = .1389). Grade = 3 adverse events were reported in 38.5% of patients who received Ona + Bev and 35.9% of patients who received Pla + Bev. Exploratory biomarker analyses suggested that patients with high expression of hepatocyte growth factor or unmethylated O(6)-methylguanine-DNA methyltransferase may benefit from Ona + Bev. Conclusion There was no evidence of further clinical benefit with the addition of onartuzumab to bevacizumab compared with bevacizumab plus placebo in unselected patients with recurrent glioblastoma in this phase II study; however, further investigation into biomarker subgroups is warranted.
Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials.
Authors:Ellingson BM; Harris RJ; Woodworth DC; Leu K; Zaw O; Mason WP; Sahebjam S; Abrey LE; Aftab DT; Schwab GM; Hessel C; Lai A; Nghiemphu PL; Pope WB; Wen PY; Cloughesy TF;
Abstract:Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy.
Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma.
Source:Journal of neuro-oncology
Authors:Pan E; Supko JG; Kaley TJ; Butowski NA; Cloughesy T; Jung J; Desideri S; Grossman S; Ye X; Park DM;
Abstract:Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.
An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers.
Source:Cancer cell
Authors:Villa GR; Hulce JJ; Zanca C; Bi J; Ikegami S; Cahill GL; Gu Y; Lum KM; Masui K; Yang H; Rong X; Hong C; Turner KM; Liu F; Hon GC; Jenkins D; Martini M; Armando AM; Quehenberger O; Cloughesy TF; Furnari FB; Cavenee WK; Tontonoz P; Gahman TC; Shiau AK; Cravatt BF; Mischel PS;
Abstract:Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRa-partial/LXRß-full agonist selectively kills GBM cells in an LXRß- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.
Biomarkers in NOA-04: another piece to the puzzle.
Authors:Lassman AB; Cloughesy TF;
Simulation, phantom validation, and clinical evaluation of fast pH-weighted molecular imaging using amine chemical exchange saturation transfer echo planar imaging (CEST-EPI) in glioma at 3?T.
Source:NMR in biomedicine
Authors:Harris RJ; Cloughesy TF; Liau LM; Nghiemphu PL; Lai A; Pope WB; Ellingson BM;
Abstract:Acidity within the extracellular milieu is a hallmark of cancer. There is a current need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. Chemical exchange saturation transfer (CEST) MRI targeting fast-exchanging amine protons can be used to obtain high-resolution pH-weighted images, but conventional CEST acquisition strategies are slow. There is also a need for more accurate MR simulations to better understand the effects of amine CEST pulse sequence parameters on pH-weighted image contrast. In the current study we present a simulation of amine CEST contrast specific for a newly developed CEST echoplanar imaging (EPI) pulse sequence. The accuracy of the simulations was validated by comparing the exchange rates and Z-spectrum under a variety of conditions using physical phantoms of glutamine with different pH values. The effects of saturation pulse shapes, pulse durations, pulse train lengths, repetition times, and relaxation rates of bulk water and exchangeable amine protons on the CEST signal were explored for normal-appearing white matter (NAWM), glioma, and cerebrospinal fluid. Last, 18 patients with WHO II-IV gliomas were evaluated. Results showed that the Z-spectrum was highly dependent on saturation pulse shape, repetition time, saturation amplitude, magnetic field strength, and T2 within bulk water; however, the Z-spectrum was only minimally influenced by saturation pulse duration and the specific relaxation rates of amine protons. Results suggest that a Gaussian saturation pulse train consisting of 3 × 100 ms pulses using the minimum allowable repetition time is optimal for achieving over 90% available contrast across all tissues. Results also demonstrate that high saturation pulse amplitude and scanner field strength (>3?T) are necessary for adequate endogenous pH-weighted amine CEST contrast. pH-weighted amine CEST contrast increased with increasing tumor grade, with glioblastoma showing significantly higher contrast compared with WHO II or III gliomas.
Bidirectional Contrast agent leakage correction of dynamic susceptibility contrast (DSC)-MRI improves cerebral blood volume estimation and survival prediction in recurrent glioblastoma treated with bevacizumab.
Source:Journal of magnetic resonance imaging : JMRI
Authors:Leu K; Boxerman JL; Lai A; Nghiemphu PL; Pope WB; Cloughesy TF; Ellingson BM;
Abstract:Accounting for T1 and T2* leakage contamination in DSC-MRI using a two-compartment, bidirectional rather than unidirectional exchange model might improve post-bevacizumab survival stratification in patients with recurrent GBM. J. Magn. Reson. Imaging 2016;44:1229-1237.
Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma.
Authors:Wick W; Chinot OL; Bendszus M; Mason W; Henriksson R; Saran F; Nishikawa R; Revil C; Kerloeguen Y; Cloughesy T;
Abstract:Pseudoprogression complicated progression assessment in a small but relevant number of patients but had negligible impact on PFS. Bevacizumab did not appear to adversely impact tumor progression patterns.
Large-scale assessment of the gliomasphere model system.
Authors:Laks DR; Crisman TJ; Shih MY; Mottahedeh J; Gao F; Sperry J; Garrett MC; Yong WH; Cloughesy TF; Liau LM; Lai A; Coppola G; Kornblum HI;
Abstract:This comprehensive assessment reveals advantages and limitations of using gliomaspheres to model GBM biology, and provides a novel strategy for selecting genes for future study.
Reply to F. Felix et al and M.F. Fay et al.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Happold C; Gorlia T; Chinot O; Gilbert MR; Nabors LB; Wick W; Pugh SL; Hegi M; Cloughesy T; Roth P; Reardon DA; Perry JR; Mehta MP; Stupp R; Weller M;
Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio.
Authors:Chinot OL; Nishikawa R; Mason W; Henriksson R; Saran F; Cloughesy T; Garcia J; Revil C; Abrey L; Wick W;
Abstract:This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.
Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.
Authors:Nguyen HN; Lie A; Li T; Chowdhury R; Liu F; Ozer B; Wei B; Green RM; Ellingson BM; Wang HJ; Elashoff R; Liau LM; Yong WH; Nghiemphu PL; Cloughesy T; Lai A;
Abstract:The prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
Improved Leakage Correction for Single-Echo Dynamic Susceptibility Contrast Perfusion MRI Estimates of Relative Cerebral Blood Volume in High-Grade Gliomas by Accounting for Bidirectional Contrast Agent Exchange.
Source:AJNR. American journal of neuroradiology
Authors:Leu K; Boxerman JL; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB; Ellingson BM;
Abstract:Inclusion of the bidirectional exchange in leakage-correction models for single-echo DSC MR imaging improves the model fit to leakage-contaminated DSC MR imaging data and significantly improves the estimation of relative CBV in high-grade gliomas.
PD-1 blockade enhances the vaccination-induced immune response in glioma.
Source:JCI insight
Authors:Antonios JP; Soto H; Everson RG; Orpilla J; Moughon D; Shin N; Sedighim S; Yong WH; Li G; Cloughesy TF; Liau LM; Prins RM;
Abstract:DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8(+) T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.
Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy.
Authors:Saran F; Chinot OL; Henriksson R; Mason W; Wick W; Cloughesy T; Dhar S; Pozzi E; Garcia J; Nishikawa R;
Abstract:The safety profile was consistent with that expected from radiotherapy/temozolomide plus bevacizumab. The increased AE incidence with bevacizumab did not impact patients' ability to receive standard-of-care treatment or to undergo further surgery.
Prioritization schema for immunotherapy clinical trials in glioblastoma.
Authors:Hodges TR; Ferguson SD; Caruso HG; Kohanbash G; Zhou S; Cloughesy TF; Berger MS; Poste GH; Khasraw M; Ba S; Jiang T; Mikkelson T; Yung WK; de Groot JF; Fine H; Cantley LC; Mellinghoff IK; Mitchell DA; Okada H; Heimberger AB;
Abstract:The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.
Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.
Source:Science translational medicine
Authors:Cloughesy TF; Landolfi J; Hogan DJ; Bloomfield S; Carter B; Chen CC; Elder JB; Kalkanis SN; Kesari S; Lai A; Lee IY; Liau LM; Mikkelsen T; Nghiemphu PL; Piccioni D; Walbert T; Chu A; Das A; Diago OR; Gammon D; Gruber HE; Hanna M; Jolly DJ; Kasahara N; McCarthy D; Mitchell L; Ostertag D; Robbins JM; Rodriguez-Aguirre M; Vogelbaum MA;
Abstract:Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).
Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.
Source:Journal of neuro-oncology
Authors:Panosyan EH; Lasky JL; Lin HJ; Lai A; Hai Y; Guo X; Quinn M; Nelson SF; Cloughesy TF; Nghiemphu PL;
Abstract:Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.
Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.
Source:Cancer cell
Authors:Wei W; Shin YS; Xue M; Matsutani T; Masui K; Yang H; Ikegami S; Gu Y; Herrmann K; Johnson D; Ding X; Hwang K; Kim J; Zhou J; Su Y; Li X; Bonetti B; Chopra R; James CD; Cavenee WK; Cloughesy TF; Mischel PS; Heath JR; Gini B;
Abstract:Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.
Reply to T.J. Kruser et al.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Chinot OL; Taphoorn MJ; Bais C; Bourgon R; Phillips HS; Abrey LE; Wick W; Mason W; Henriksson R; Saran F; Nishikawa R; Cloughesy T;
Reply to comment on: 'Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach'.
Source:Physics in medicine and biology
Authors:Rockne R; Rockhill JK; Mrugala M; Spence AM; Kalet I; Hendrickson K; Lai A; Cloughesy T; Alvord EC; Swanson KR;
Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study.
Authors:Butowski N; Colman H; De Groot JF; Omuro AM; Nayak L; Wen PY; Cloughesy TF; Marimuthu A; Haidar S; Perry A; Huse J; Phillips J; West BL; Nolop KB; Hsu HH; Ligon KL; Molinaro AM; Prados M;
Abstract:PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Happold C; Gorlia T; Chinot O; Gilbert MR; Nabors LB; Wick W; Pugh SL; Hegi M; Cloughesy T; Roth P; Reardon DA; Perry JR; Mehta MP; Stupp R; Weller M;
Abstract:The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.
Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas.
Authors:Schiff D; Desjardins A; Cloughesy T; Mikkelsen T; Glantz M; Chamberlain MC; Reardon DA; Wen PY;
Abstract:Cabozantinib at a dose of 40?mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40?mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma.
The Impact of T2/FLAIR Evaluation per RANO Criteria on Response Assessment of Recurrent Glioblastoma Patients Treated with Bevacizumab.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Huang RY; Rahman R; Ballman KV; Felten SJ; Anderson SK; Ellingson BM; Nayak L; Lee EQ; Abrey LE; Galanis E; Reardon DA; Pope WB; Cloughesy TF; Wen PY;
Abstract:The inclusion of T2/FLAIR assessment resulted in statistically significant differences in median PFS and ORRs compared with assessment of solely enhancing tumor (Macdonald criteria), although OR and PFS determined by both RANO and Macdonald criteria correlated with OS.
Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma.
Source:Current neurology and neuroscience reports
Authors:Clark PM; Mai WX; Cloughesy TF; Nathanson DA;
Abstract:Malignant gliomas are intractable and among the most lethal human malignancies. Like other cancers, metabolic reprogramming is a key feature of glioma and is thought to accommodate the heightened nutrient requirements for tumor cell proliferation, growth, and survival. This metabolic rewiring, driven by oncogenic signaling and molded by the unique environment of the brain, may impose vulnerabilities that could be exploited therapeutically for increased tumor control. In this review, we discuss the prominent metabolic features of malignant glioma, the key pathways regulating glioma metabolism, and the potential therapeutic opportunities for targeting metabolic processes.
The MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide.
Authors:Rapkins RW; Wang F; Nguyen HN; Cloughesy TF; Lai A; Ha W; Nowak AK; Hitchins MP; McDonald KL;
Abstract:The T allele of the rs16906252 SNP is a key determinant in the acquisition of MGMT methylation in glioblastoma. Temozolomide-treated patients with the rs16906252 T genotype have better survival, irrespective of tumor methylation status.
Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide.
Source:Molecular cancer
Authors:Tso JL; Yang S; Menjivar JC; Yamada K; Zhang Y; Hong I; Bui Y; Stream A; McBride WH; Liau LM; Nelson SF; Cloughesy TF; Yong WH; Lai A; Tso CL;
Abstract:These data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT.
pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI.
Authors:Harris RJ; Cloughesy TF; Liau LM; Prins RM; Antonios JP; Li D; Yong WH; Pope WB; Lai A; Nghiemphu PL; Ellingson BM;
Abstract:Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.
EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling.
Source:Molecular cell
Authors:Liu F; Hon GC; Villa GR; Turner KM; Ikegami S; Yang H; Ye Z; Li B; Kuan S; Lee AY; Zanca C; Wei B; Lucey G; Jenkins D; Zhang W; Barr CL; Furnari FB; Cloughesy TF; Yong WH; Gahman TC; Shiau AK; Cavenee WK; Ren B; Mischel PS;
Abstract:Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.
Quantification of Nonenhancing Tumor Burden in Gliomas Using Effective T2 Maps Derived from Dual-Echo Turbo Spin-Echo MRI.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Ellingson BM; Lai A; Nguyen HN; Nghiemphu PL; Pope WB; Cloughesy TF;
Abstract:T2 maps using dual-echo data are feasible, stable, and can be used to objectively define NET burden for use in brain tumor characterization, prognosis, and response assessment. The use of effective T2 maps for defining NET burden should be validated in a randomized, clinical trial.
Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma.
Authors:Wen PY; Omuro A; Ahluwalia MS; Fathallah-Shaykh HM; Mohile N; Lager JJ; Laird AD; Tang J; Jiang J; Egile C; Cloughesy TF;
Abstract:Voxtalisib in combination with TMZ with or without RT in patients with high-grade gliomas demonstrated a favorable safety profile and a moderate level of PI3K/mTOR pathway inhibition.
Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Sandmann T; Bourgon R; Garcia J; Li C; Cloughesy T; Chinot OL; Wick W; Nishikawa R; Mason W; Henriksson R; Saran F; Lai A; Moore N; Kharbanda S; Peale F; Hegde P; Abrey LE; Phillips HS; Bais C;
Abstract:Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.
Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials.
Authors:Ellingson BM; Bendszus M; Boxerman J; Barboriak D; Erickson BJ; Smits M; Nelson SJ; Gerstner E; Alexander B; Goldmacher G; Wick W; Vogelbaum M; Weller M; Galanis E; Kalpathy-Cramer J; Shankar L; Jacobs P; Pope WB; Yang D; Chung C; Knopp MV; Cha S; van den Bent MJ; Chang S; Yung WK; Cloughesy TF; Wen PY; Gilbert MR;
Abstract:A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems.
2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.
Source:Cell metabolism
Authors:Fu X; Chin RM; Vergnes L; Hwang H; Deng G; Xing Y; Pai MY; Li S; Ta L; Fazlollahi F; Chen C; Prins RM; Teitell MA; Nathanson DA; Lai A; Faull KF; Jiang M; Clarke SG; Cloughesy TF; Graeber TG; Braas D; Christofk HR; Jung ME; Reue K; Huang J;
Abstract:We discovered recently that the central metabolite a-ketoglutarate (a-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various a-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like a-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or a-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.
Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.
Source:Tomography : a journal for imaging research
Authors:Chang W; Pope WB; Harris RJ; Hardy AJ; Leu K; Mody RR; Nghiemphu PL; Lai A; Cloughesy TF; Ellingson BM;
Abstract:The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um(2)/ms and ADCH value of 1.6 um(2)/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ.
Toward precision medicine in glioblastoma: the promise and the challenges.
Authors:Prados MD; Byron SA; Tran NL; Phillips JJ; Molinaro AM; Ligon KL; Wen PY; Kuhn JG; Mellinghoff IK; de Groot JF; Colman H; Cloughesy TF; Chang SM; Ryken TC; Tembe WD; Kiefer JA; Berens ME; Craig DW; Carpten JD; Trent JM;
Abstract:Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system.
Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Masui K; Tanaka K; Ikegami S; Villa GR; Yang H; Yong WH; Cloughesy TF; Yamagata K; Arai N; Cavenee WK; Mischel PS;
Abstract:Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Taphoorn MJ; Henriksson R; Bottomley A; Cloughesy T; Wick W; Mason WP; Saran F; Nishikawa R; Hilton M; Theodore-Oklota C; Ravelo A; Chinot OL;
Abstract:The addition of bevacizumab to standard-of-care treatment for newly diagnosed glioblastoma had no impact on HRQoL during the progression-free period.
Patient-specific characterization of the invasiveness and proliferation of low-grade gliomas using serial MR imaging and a mathematical model of tumor growth.
Source:Oncology reports
Authors:Hathout L; Ellingson BM; Cloughesy TF; Pope WB;
Abstract:Low-grade gliomas (LGGs) represent a significant proportion of hemispheric gliomas in adults. Although less aggressive than glioblastomas (GBMs), they have a broad range of biologic behavior, and often a limited prognosis. The aim of the present study was to explore LGG growth kinetics through a combination of routine MRI imaging and a novel adaptation of a mathematical tumor model. MRI imaging in 14 retrospectively identified grade II LGGs that showed some tumor enhancement was used to assess tumor radii at two separate time-points. This information was combined with a reaction-diffusion partial-differential equation model of tumor growth to calculate diffusion (D) and proliferation (?) coefficients for each tumor, representing measures of tumor invasiveness and cellular multiplication, respectively. The results were compared to previously published data on GBMs. The average value of D was 0.034 mm(2)/day and ? was 0.0056/day. Grade II LGGs had a broad range of D and ?. On average, the proliferation coefficient ? was significantly lower than previously published values for GBM, by about an order of magnitude. The diffusion coefficient, modeling invasiveness, however, was only slightly lower but without statistical significance. It was possible to calculate detailed growth kinetic parameters for some LGGs, potentially providing a new way to assess tumor aggressiveness and possibly gauge prognosis. Even within a single-grade (WHO II), LGGs were found to have broad range of D and ?, possibly correlating to their variable biologic behavior. Overall, the model parameters suggest that LGG is less aggressive than GBM based primarily on a lower index of tumor proliferation rather than on lesser invasiveness.
Relationship Between [18F]FDOPA PET Uptake, Apparent Diffusion Coefficient (ADC), and Proliferation Rate in Recurrent Malignant Gliomas.
Source:Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging
Authors:Karavaeva E; Harris RJ; Leu K; Shabihkhani M; Yong WH; Pope WB; Lai A; Nghiemphu PL; Liau LM; Chen W; Czernin J; Cloughesy TF; Ellingson BM;
Abstract:A significant association may exist between [(18)F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma.
Source:Nature reviews. Cancer
Authors:Furnari FB; Cloughesy TF; Cavenee WK; Mischel PS;
Abstract:As tumours evolve, the daughter cells of the initiating cell often become molecularly heterogeneous and develop different functional properties and therapeutic vulnerabilities. In glioblastoma (GBM), a lethal form of brain cancer, the heterogeneous expression of the epidermal growth factor receptor (EGFR) poses a substantial challenge for the effective use of EGFR-targeted therapies. Understanding the mechanisms that cause EGFR heterogeneity in GBM should provide better insights into how they, and possibly other amplified receptor tyrosine kinases, affect cellular signalling, metabolism and drug resistance.
MRI perfusion measurements calculated using advanced deconvolution techniques predict survival in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Authors:Harris RJ; Cloughesy TF; Hardy AJ; Liau LM; Pope WB; Nghiemphu PL; Lai A; Ellingson BM;
Abstract:Bevacizumab is a therapeutic drug used in treatment of recurrent glioblastoma to inhibit angiogenesis. Treatment response is often monitored through the use of perfusion MRI measures of cerebral blood volume, flow, and other pharmacokinetic parameters; however, most methods for deriving these perfusion parameters can produce errors depending on bolus kinetics. Recently, a number of new methods have been developed to overcome these challenges. In the current study we examine cerebral blood volume and blood flow characteristics in 45 recurrent glioblastoma patients before and after treatment with bevacizumab. Perfusion MRI data was processed using a standard single value decomposition (SVD) technique, two block-circulant SVD techniques, and a Bayesian estimation technique. A proportional hazards model showed that patients with a large decrease in relative blood volume (RBV) after treatment had extended overall survival (P = 0.0048). Patients with large pre-treatment relative blood flow (RBF) showed extended progression-free survival (P = 0.0216) and overall survival (P = 0.0112), and patients with a large decrease in RBF following treatment showed extended overall survival (P = 0.0049). These results provide evidence that blood volume and blood flow measurements can be used as biomarkers in patients treated with bevacizumab.
Arterial spin-labeling perfusion MRI stratifies progression-free survival and correlates with epidermal growth factor receptor status in glioblastoma.
Source:AJNR. American journal of neuroradiology
Authors:Qiao XJ; Ellingson BM; Kim HJ; Wang DJ; Salamon N; Linetsky M; Sepahdari AR; Jiang B; Tian JJ; Esswein SR; Cloughesy TF; Lai A; Nghiemphu L; Pope WB;
Abstract:Qualitative evaluation of arterial spin-labeling CBF maps can be used to stratify survival and predict epidermal growth factor receptor variant III expression in patients with glioblastoma.
A novel bicompartmental mathematical model of glioblastoma multiforme.
Source:International journal of oncology
Authors:Hathout L; Ellingson BM; Cloughesy T; Pope WB;
Abstract:Glioblastoma multiforme (GBM) is the most common primary CNS neoplasm, and continues to have a dismal prognosis. A widely-used approach to the mathematical modeling of GBM involves utilizing a reaction-diffusion model of cell density as a function of space and time, which accounts for both the infiltrative nature of the tumor using a diffusion term, and the proliferation of tumor cells using a proliferation term. The current paper extends the standard models by incorporating an advection term to account for the so-called 'cell streaming' which is often seen with GBM, where some of the tumor cells seem to stream widely along the white matter pathways. The current paper introduces a bicompartmental GBM model in the form of coupled partial differential equations with a component of dispersive cells. The parameters needed for this model are explored. It is shown that this model can account for the rapid distant dispersal of GBM cells in the CNS, as well as such phenomena as multifocal gliomas with tumor foci distant from the core tumor site. The model suggests a higher percentage of tumor cells below the threshold of MRI images in comparison to the standard model. By incorporating an advection component, the proposed model is able to account for phenomena such as multicentric gliomas and rapid distant dispersion of a small fraction of tumor cells throughout the CNS, features important to the prognosis of GBM, but not easily accounted for by current models.
Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group.
Authors:Alexander BM; Galanis E; Yung WK; Ballman KV; Boyett JM; Cloughesy TF; Degroot JF; Huse JT; Mann B; Mason W; Mellinghoff IK; Mikkelsen T; Mischel PS; O'Neill BP; Prados MD; Sarkaria JN; Tawab-Amiri A; Trippa L; Ye X; Ligon KL; Berry DA; Wen PY;
Abstract:Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.
Emerging function of mTORC2 as a core regulator in glioblastoma: metabolic reprogramming and drug resistance.
Source:Cancer biology & medicine
Authors:Wu SH; Bi JF; Cloughesy T; Cavenee WK; Mischel PS;
Abstract:Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses define the molecular architecture of GBM and highlight a central function for mechanistic target of rapamycin (mTOR) signaling. mTOR kinase exists in two multi-protein complexes, namely, mTORC1 and mTORC2. These complexes differ in terms of function, regulation and rapamycin sensitivity. mTORC1 is well established as a cancer drug target, whereas the functions of mTORC2 in cancer, including GBM, remains poorly understood. This study reviews the recent findings that demonstrate a central function of mTORC2 in regulating tumor growth, metabolic reprogramming, and targeted therapy resistance in GBM, which makes mTORC2 as a critical GBM drug target.
Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Li S; Chowdhury R; Liu F; Chou AP; Li T; Mody RR; Lou JJ; Chen W; Reiss J; Soto H; Prins R; Liau LM; Mischel PS; Nghiemphu PL; Yong WH; Cloughesy TF; Lai A;
Abstract:We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.
Hypervascular tumor volume estimated by comparison to a large-scale cerebral blood volume radiographic atlas predicts survival in recurrent glioblastoma treated with bevacizumab.
Source:Cancer imaging : the official publication of the International Cancer Imaging Society
Authors:Leu K; Enzmann DR; Woodworth DC; Harris RJ; Tran AN; Lai A; Nghiemphu PL; Pope WB; Cloughesy TF; Ellingson BM;
Abstract:This study highlights the advantages of large-scale population maps to identify abnormal biological tissues.
Recursive partitioning analysis of prognostic variables in newly diagnosed anaplastic oligodendroglial tumors.
Authors:Panageas KS; Reiner AS; Iwamoto FM; Cloughesy TF; Aldape KD; Rivera AL; Eichler AF; Louis DN; Paleologos NA; Fisher BJ; Ashby LS; Cairncross JG; Urgoiti GB; Wen PY; Ligon KL; Schiff D; Robins HI; Rocque BG; Chamberlain MC; Mason WP; Weaver SA; Green RM; Kamar FG; Abrey LE; DeAngelis LM; Jhanwar SC; Rosenblum MK; Lassman AB;
Abstract:These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome.
Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials neuroimaging endpoint workshop (January 30, 2014, Bethesda MD).
Authors:Wen PY; Cloughesy TF; Ellingson BM; Reardon DA; Fine HA; Abrey L; Ballman K; Bendszuz M; Buckner J; Chang SM; Prados MD; Pope WB; Gregory Sorensen A; van den Bent M; Yung WK;
Abstract:On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons, biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters.
Pros and cons of current brain tumor imaging.
Authors:Ellingson BM; Wen PY; van den Bent MJ; Cloughesy TF;
Abstract:Over the past 20 years, very few agents have been approved for the treatment of brain tumors. Recent studies have highlighted some of the challenges in assessing activity in novel agents for the treatment of brain tumors. This paper reviews some of the key challenges related to assessment of tumor response to therapy in adult high-grade gliomas and discusses the strengths and limitations of imaging-based endpoints. Although overall survival is considered the "gold standard" endpoint in the field of oncology, progression-free survival and response rate are endpoints that hold great value in neuro-oncology. Particular focus is given to advancements made since the January 2006 Brain Tumor Endpoints Workshop, including the development of Response Assessment in Neuro-Oncology criteria, the value of T2/fluid-attenuated inversion recovery, use of objective response rates and progression-free survival in clinical trials, and the evaluation of pseudoprogression, pseudoresponse, and inflammatory response in radiographic images.
Treatment response evaluation using 18F-FDOPA PET in patients with recurrent malignant glioma on bevacizumab therapy.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Schwarzenberg J; Czernin J; Cloughesy TF; Ellingson BM; Pope WB; Grogan T; Elashoff D; Geist C; Silverman DH; Phelps ME; Chen W;
Abstract:(18)F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.
Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy.
Authors:Piccioni DE; Selfridge J; Mody RR; Chowdhury R; Li S; Lalezari S; Wawrzynski J; Quan J; Zurayk M; Chou AP; Sanchez DE; Liau LM; Ellingson BM; Pope WB; Nghiemphu PL; Green RM; Wang HJ; Yong WH; Elashoff R; Cloughesy TF; Lai A;
Abstract:Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients.
¹8F-FLT ???and ¹8F-FDOPA PET kinetics in recurrent brain tumors.
Source:European journal of nuclear medicine and molecular imaging
Authors:Wardak M; Schiepers C; Cloughesy TF; Dahlbom M; Phelps ME; Huang SC;
Abstract:For recurrent malignant glioma treated with bevacizumab and irinotecan, FLT kinetic parameters obtained early after the start of treatment (absolute values and their associated changes) can provide sufficient information to predict OS with reasonable confidence using MLR. The slight increase in accuracy for predicting OS with a combination of FLT and FDOPA PET information may not warrant the additional acquisition of FDOPA PET for therapy monitoring in patients with recurrent glioma.
Bevacizumab for newly diagnosed glioblastoma.
Source:The New England journal of medicine
Authors:Chinot OL; Wick W; Cloughesy T;
Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors.
Source:Molecular cancer research : MCR
Authors:Panosyan EH; Wang Y; Xia P; Lee WN; Pak Y; Laks DR; Lin HJ; Moore TB; Cloughesy TF; Kornblum HI; Lasky JL 3rd;
Abstract:Findings have potential impact for providing adjuvant means to enhance brain tumor chemotherapy.
Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial.
Authors:Ellingson BM; Kim HJ; Woodworth DC; Pope WB; Cloughesy JN; Harris RJ; Lai A; Nghiemphu PL; Cloughesy TF;
Abstract:Use of CE T1-weighted subtraction maps improved visualization and aided better prediction of patient survival in recurrent GBM treated with bevacizumab compared with conventional segmentation of CE T1-weighted images. Clinical trial registration no. NCT00345163. Online supplemental material is available for this article.
Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02.
Authors:Wen PY; Chang SM; Lamborn KR; Kuhn JG; Norden AD; Cloughesy TF; Robins HI; Lieberman FS; Gilbert MR; Mehta MP; Drappatz J; Groves MD; Santagata S; Ligon AH; Yung WK; Wright JJ; Dancey J; Aldape KD; Prados MD; Ligon KL;
Abstract:Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
Comparison of visual and semiquantitative analysis of 18F-FDOPA-PET/CT for recurrence detection in glioblastoma patients.
Authors:Herrmann K; Czernin J; Cloughesy T; Lai A; Pomykala KL; Benz MR; Buck AK; Phelps ME; Chen W;
Abstract:Both visual and semiquantitative indices detected glioblastoma recurrence with high accuracy and were predictive for PFS. Lesion-to-normal-tissue ratios were the best discriminators of PFS; however, none of the investigated parameters predicted OS. These retrospectively established analysis parameters need to be confirmed prospectively.
Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma.
Source:AJNR. American journal of neuroradiology
Authors:Ellingson BM; Sahebjam S; Kim HJ; Pope WB; Harris RJ; Woodworth DC; Lai A; Nghiemphu PL; Mason WP; Cloughesy TF;
Abstract:The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 µm(2)/ms have a survival advantage when treated with bevacizumab.
Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry.
Authors:Tran AN; Lai A; Li S; Pope WB; Teixeira S; Harris RJ; Woodworth DC; Nghiemphu PL; Cloughesy TF; Ellingson BM;
Abstract:The current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.
The procurement, storage, and quality assurance of frozen blood and tissue biospecimens in pathology, biorepository, and biobank settings.
Source:Clinical biochemistry
Authors:Shabihkhani M; Lucey GM; Wei B; Mareninov S; Lou JJ; Vinters HV; Singer EJ; Cloughesy TF; Yong WH;
Abstract:Well preserved frozen biospecimens are ideal for evaluating the genome, transcriptome, and proteome. While papers reviewing individual aspects of frozen biospecimens are available, we present a current overview of experimental data regarding procurement, storage, and quality assurance that can inform the handling of frozen biospecimens. Frozen biospecimen degradation can be influenced by factors independent of the collection methodology including tissue type, premortem agonal changes, and warm ischemia time during surgery. Rapid stabilization of tissues by snap freezing immediately can mitigate artifactually altered gene expression and, less appreciated, protein phosphorylation profiles. Collection protocols may be adjusted for specific tissue types as cellular ischemia tolerance varies widely. If data is not available for a particular tissue type, a practical goal is snap freezing within 20min. Tolerance for freeze-thaw events is also tissue type dependent. Tissue storage at -80°C can preserve DNA and protein for years but RNA can show degradation at 5years. For -80°C freezers, aliquots frozen in RNAlater or similar RNA stabilizing solutions are a consideration. It remains unresolved as to whether storage at -150°C provides significant advantages relative to that at -80°C. Histologic quality assurance of tissue biospecimens is typically performed at the time of surgery but should also be conducted on the aliquot to be distributed because of tissue heterogeneity. Biobanking protocols for blood and its components are highly dependent on intended use and multiple collection tube types may be needed. Additional quality assurance testing should be dictated by the anticipated downstream applications.
C-terminally truncated form of aB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma.
Source:Journal of neuro-oncology
Authors:Avliyakulov NK; Rajavel KS; Le KM; Guo L; Mirsadraei L; Yong WH; Liau LM; Li S; Lai A; Nghiemphu PL; Cloughesy TF; Linetsky M; Haykinson MJ; Pope WB;
Abstract:Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of aB-crystallin, a small heat-shock and anti-apoptotic protein. aB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and aB-crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of aB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of aB-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C-terminally truncated form of aB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma.
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
Source:The New England journal of medicine
Authors:Chinot OL; Wick W; Mason W; Henriksson R; Saran F; Nishikawa R; Carpentier AF; Hoang-Xuan K; Kavan P; Cernea D; Brandes AA; Hilton M; Abrey L; Cloughesy T;
Abstract:The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; number, NCT00943826.).
Short-interval estimation of proliferation rate using serial diffusion MRI predicts progression-free survival in newly diagnosed glioblastoma treated with radiochemotherapy.
Source:Journal of neuro-oncology
Authors:Zaw TM; Pope WB; Cloughesy TF; Lai A; Nghiemphu PL; Ellingson BM;
Abstract:Cell invasion, motility, and proliferation level estimate (CIMPLE) mapping is a new imaging technique that provides parametric maps of microscopic invasion and proliferation rate estimates using serial diffusion MRI data. However, a few practical constraints have limited the use of CIMPLE maps as a tool for estimating these dynamic parameters, particularly during short-interval follow-up times. The purpose of the current study was to develop an approximation for the CIMPLE map solution for short-interval scanning involving the assumption that net intervoxel tumor invasion does not occur within sufficiently short time frames. Proliferation rate maps created using the "no invasion" approximation were found to be increasingly similar to maps created from full solution during increasingly longer follow-up intervals (3D cross correlation, R (2) = 0.5298, P = 0.0001). Results also indicate proliferation rate maps from the "no invasion" approximation had significantly higher sensitivity (82 vs. 64%) and specificity (90 vs. 80%) for predicting 6 month progression free survival and was a better predictor of time to progression during standard radiochemotherapy compared to the full CIMPLE solution (log-rank; no invasion estimation, P = 0.0134; full solution, P = 0.0555). Together, results suggest the "no invasion" approximation allows for quick estimation of proliferation rate using diffusion MRI data obtained from multiple scans obtained daily or biweekly for use in quantifying early treatment response.
Nonlinear distortion correction of diffusion MR images improves quantitative DTI measurements in glioblastoma.
Source:Journal of neuro-oncology
Authors:Woodworth DC; Pope WB; Liau LM; Kim HJ; Lai A; Nghiemphu PL; Cloughesy TF; Ellingson BM;
Abstract:The purpose of this study was to use a retrospective nonlinear distortion correction technique and evaluate the changes in DTI metrics in areas of interest in and around GBM tumors. A total of 24 histologically confirmed GBM patients with pre-operative 20-direction DTI scans were examined. Variability in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in normal tissue before and after distortion correction were examined. Changes in mean, median and variance of ADC and FA in contrast enhancing and T2/FLAIR ROIs were also examined with and without distortion correction. Results suggest the intra-subject SDs of ADC and FA decreased in normal tissue after the application of distortion correction (P < 0.0001). FA mean and median values decreased after distortion correction in both T1+C and T2 ROIs (P < 0.017), while ADC mean and median values did not significantly change except for the median ADC in T1+C ROIs (P = 0.0054). The intra-subject SD of ADC and FA values in tumor ROIs changed significantly with distortion correction, and Bland-Altman analysis indicated that the bias and the SD of the bias of these intra-subject SDs were larger than those of the mean and median terms. Additionally, the means of the two curves of a double Gaussian fit to the histogram of ADC values from T1+C ROIs, ADCL (mean of lower Gaussian) as well as ADCH (mean of the higher Gaussian) were found to change significantly with distortion correction (P = 0.0045 for ADCL and P = 0.0370 for ADCH). Nonlinear distortion correction better aligns neuro-anatomical structures between DTI and anatomical scans, and significantly alters the measurement of values within tumor ROIs for GBM patients.
Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA.
Source:Science (New York, N.Y.)
Authors:Nathanson DA; Gini B; Mottahedeh J; Visnyei K; Koga T; Gomez G; Eskin A; Hwang K; Wang J; Masui K; Paucar A; Yang H; Ohashi M; Zhu S; Wykosky J; Reed R; Nelson SF; Cloughesy TF; James CD; Rao PN; Kornblum HI; Heath JR; Cavenee WK; Furnari FB; Mischel PS;
Abstract:Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.
Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) low-grade glioma research workshop.
Authors:Huse JT; Wallace M; Aldape KD; Berger MS; Bettegowda C; Brat DJ; Cahill DP; Cloughesy T; Haas-Kogan DA; Marra M; Miller CR; Nelson SJ; Salama SR; Soffietti R; Wen PY; Yip S; Yen K; Costello JF; Chang S;
Abstract:Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC(2)) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology.
Altered functional connectivity of the default mode network in diffuse gliomas measured with pseudo-resting state fMRI.
Source:Journal of neuro-oncology
Authors:Harris RJ; Bookheimer SY; Cloughesy TF; Kim HJ; Pope WB; Lai A; Nghiemphu PL; Liau LM; Ellingson BM;
Abstract:The purpose of the current study was to explore whether brain tumors disrupt the integrity of the default mode network (DMN), a well-characterized resting-state fMRI network. We evaluated whether tumor grade, volume, post-surgical/clinical status, or location decreased the functional connectivity within the DMN in patients with gliomas. Task-based fMRI data was obtained from 68 diffuse glioma patients and 12 healthy volunteers. Pseudo-resting state fMRI data was calculated from task-based fMRI data using standard techniques. Data was preprocessed and DMN integrity was compared across WHO grade, tumor volume surgical status (new vs. recurrent tumors), age, and KPS using univariate and multivariate linear models. WHO grade was the most significant predictor of DMN integrity (P = 0.004), whereas T2 hyperintense lesion volume was not a predictor (P = 0.154). DMN integrity was lower in high-grade (WHO III–IV) compared with low-grade (WHO II) patients (P = 0.020). Tumors in the left parietal lobe showed a more impaired DMN compared with tumors in the frontal lobe, while tumors within and outside the network nodes did not differ significantly. Results suggest higher tumor grade along with prior surgery and/or treatment cause the largest reduction in DMN functional connectivity in patients with primary gliomas, and that tumor location has an impact on connectivity.
mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.
Source:Cell metabolism
Authors:Masui K; Tanaka K; Akhavan D; Babic I; Gini B; Matsutani T; Iwanami A; Liu F; Villa GR; Gu Y; Campos C; Zhu S; Yang H; Yong WH; Cloughesy TF; Mellinghoff IK; Cavenee WK; Shaw RJ; Mischel PS;
Abstract:Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Gini B; Zanca C; Guo D; Matsutani T; Masui K; Ikegami S; Yang H; Nathanson D; Villa GR; Shackelford D; Zhu S; Tanaka K; Babic I; Akhavan D; Lin K; Assuncao A; Gu Y; Bonetti B; Mortensen DS; Xu S; Raymon HK; Cavenee WK; Furnari FB; James CD; Kroemer G; Heath JR; Hege K; Chopra R; Cloughesy TF; Mischel PS;
Abstract:These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it.
PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma.
Source:Brain pathology (Zurich, Switzerland)
Authors:Phillips JJ; Aranda D; Ellison DW; Judkins AR; Croul SE; Brat DJ; Ligon KL; Horbinski C; Venneti S; Zadeh G; Santi M; Zhou S; Appin CL; Sioletic S; Sullivan LM; Martinez-Lage M; Robinson AE; Yong WH; Cloughesy T; Lai A; Phillips HS; Marshall R; Mueller S; Haas-Kogan DA; Molinaro AM; Perry A;
Abstract:High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P?=?0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.
Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis.
Source:International journal of radiation oncology, biology, physics
Authors:Lee P; Eppinga W; Lagerwaard F; Cloughesy T; Slotman B; Nghiemphu PL; Wang PC; Kupelian P; Agazaryan N; Demarco J; Selch MT; Steinberg M; Kang JJ;
Abstract:High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.
Lyophilized brain tumor specimens can be used for histologic, nucleic acid, and protein analyses after 1 year of room temperature storage.
Source:Journal of neuro-oncology
Authors:Mareninov S; De Jesus J; Sanchez DE; Kay AB; Wilson RW; Babic I; Chen W; Telesca D; Lou JJ; Mirsadraei L; Gardner TP; Khanlou N; Vinters HV; Shafa BB; Lai A; Liau LM; Mischel PS; Cloughesy TF; Yong WH;
Abstract:Frozen tissue, a gold standard biospecimen, can yield well preserved nucleic acids and proteins after over a decade but is vulnerable to thawing and has substantial fiscal, spatial, and environmental costs. A long-term room temperature biospecimen storage alternative that preserves broad analytical utility can potentially empower tissue-based research. As there is scant data on the analytical utility of lyophilized brain tumor biospecimens, we evaluated lyophilized (freeze-dried) samples stored for 1 year at room temperature. Lyophilized tumor tissue processed into paraffin sections produced good histology. Yields of extracted DNA, RNA, and protein approximated those of frozen tissue. After 1 year, lyophilized samples yielded high molecular weight DNA that permitted copy number variation analysis, IDH 1 mutation detection, and MGMT promoter methylation PCR. A 27 % decrease in RIN scores over the 1 year suggests that RNA degradation was inhibited though incompletely. Nevertheless, RT-PCR studies on lyophilized tissue performed similarly to frozen tissue. In contrast to FFPE tissues where protein bands were absent or shifted to a lower molecular weight, lyophilized samples showed similar protein bands as frozen tissue on SDS-PAGE analysis. Lyophilized tissue performed similarly to frozen tissue for Western blots and enzyme activity assays. Immunohistochemistry of lyophilized tissue that were processed into FFPE blocks often required longer incubation times for staining than standard FFPE samples but generally provided robust antigen detection. This preliminary study suggests that lyophilization has promise for long-term room temperature storage while permitting varied tests; however, further work is required to better stabilize nucleic acids particularly RNA.
EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer.
Source:Cell metabolism
Authors:Babic I; Anderson ES; Tanaka K; Guo D; Masui K; Li B; Zhu S; Gu Y; Villa GR; Akhavan D; Nathanson D; Gini B; Mareninov S; Li R; Camacho CE; Kurdistani SK; Eskin A; Nelson SF; Yong WH; Cavenee WK; Cloughesy TF; Christofk HR; Black DL; Mischel PS;
Abstract:Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept.
Source:Targeted oncology
Authors:Shonka N; Piao Y; Gilbert M; Yung A; Chang S; DeAngelis LM; Lassman AB; Liu J; Cloughesy T; Robins HI; Lloyd R; Chen A; Prados M; Wen PY; Heymach J; de Groot J;
Abstract:Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II-IV (Gr II-IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p?=?0.05. Among 28 pts, there were 116 Gr II-IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II-IV toxicity (p?=?0.002 and p?=?0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10.
Response classification based on a minimal model of glioblastoma growth is prognostic for clinical outcomes and distinguishes progression from pseudoprogression.
Source:Cancer research
Authors:Neal ML; Trister AD; Ahn S; Baldock A; Bridge CA; Guyman L; Lange J; Sodt R; Cloke T; Lai A; Cloughesy TF; Mrugala MM; Rockhill JK; Rockne RC; Swanson KR;
Abstract:Glioblastoma multiforme is the most aggressive type of primary brain tumor. Glioblastoma growth dynamics vary widely across patients, making it difficult to accurately gauge their response to treatment. We developed a model-based metric of therapy response called Days Gained that accounts for this heterogeneity. Here, we show in 63 newly diagnosed patients with glioblastoma that Days Gained scores from a simple glioblastoma growth model computed at the time of the first postradiotherapy MRI scan are prognostic for time to tumor recurrence and overall patient survival. After radiation treatment, Days Gained also distinguished patients with pseudoprogression from those with true progression. Because Days Gained scores can be easily computed with routinely available clinical imaging devices, this model offers immediate potential to be used in ongoing prospective studies.
Arsenic reverses glioblastoma resistance to mTOR-targeted therapies.
Source:Cell cycle (Georgetown, Tex.)
Authors:Iwanami A; Cloughesy TF; Cavenee WK; Mischel PS;
De-repression of PDGFRß transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients.
Source:Cancer discovery
Authors:Akhavan D; Pourzia AL; Nourian AA; Williams KJ; Nathanson D; Babic I; Villa GR; Tanaka K; Nael A; Yang H; Dang J; Vinters HV; Yong WH; Flagg M; Tamanoi F; Sasayama T; James CD; Kornblum HI; Cloughesy TF; Cavenee WK; Bensinger SJ; Mischel PS;
Abstract:These results provide the fi rst clinical and biologic evidence for receptor tyrosinekinase (RTK) "switching" as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become "addicted" to a non amplified, nonmutated, physiologically regulated RTK to evade targeted treatment.
Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy.
Source:Current neurology and neuroscience reports
Authors:Chinot OL; Macdonald DR; Abrey LE; Zahlmann G; Kerloëguen Y; Cloughesy TF;
Abstract:Since 1990, the primary criteria used for assessing response to therapy in high-grade gliomas were those developed by Macdonald and colleagues, which incorporated 2-dimensional area measurements of contrast-enhancing tumor regions, corticosteroid dosing, and clinical assessment to arrive at a designation of response, stable disease, or progression. Recent advances in imaging technology and targeted therapeutics, however, have exposed limitations of the Macdonald criteria and have highlighted the need for reevaluation of response assessment criteria. In 2010, the Response Assessment in Neuro-Oncology (RANO) Working Group published updated criteria to address this need and to standardize response assessment for high-grade gliomas. In 2009, prior to the publication of the RANO criteria, the randomized, placebo-controlled, multicenter, phase 3 AVAglio trial was designed and initiated to investigate the effectiveness of radiotherapy and temozolomide with or without bevacizumab in newly diagnosed glioblastoma. The AVAglio protocol enacted specific measures to adapt the Macdonald criteria to the frontline treatment setting and to antiangiogenic agent evaluation, including the incorporation of a T2/fluid-attenuated inversion recovery component, qualitative assessment of irregularly shaped contrast-enhancing lesions, and a decision tree for confirming or ruling out pseudoprogression. Moreover, the protocol outlines practical means by which these adapted response criteria can be implemented in the clinic. This article describes the evolution of radiographic response criteria for high-grade gliomas and highlights the similarities and differences between those implemented in the AVAglio study and those subsequently published by RANO.
Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images.
Authors:Naeini KM; Pope WB; Cloughesy TF; Harris RJ; Lai A; Eskin A; Chowdhury R; Phillips HS; Nghiemphu PL; Behbahanian Y; Ellingson BM;
Abstract:Results suggest that volume ratio may be a simple, cost-effective, and noninvasive biomarker for quickly identifying MES GBM.
Pre- and post-contrast three-dimensional double inversion-recovery MRI in human glioblastoma.
Source:Journal of neuro-oncology
Authors:Harris RJ; Cloughesy TF; Pope WB; Godinez S; Natsuaki Y; Nghiemphu PL; Meyer H; Paul D; Behbahanian Y; Lai A; Ellingson BM;
Abstract:Fluid attenuated inversion recovery (FLAIR) MRI sequences have become an indispensible tool for defining the malignant boundary in patients with brain tumors by nulling the signal contribution from cerebrospinal fluid allowing both regions of edema and regions of non-enhancing, infiltrating tumor to become hyperintense on resulting images. In the current study we examined the utility of a three-dimensional double inversion recovery (DIR) sequence that additionally nulls the MR signal associated with white matter, implemented either pre-contrast or post-contrast, in order to determine whether this sequence allows for better differentiation between tumor and normal brain tissue. T1- and T2-weighted, FLAIR, dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (rCBV), contrast-enhanced T1-weighted images (T1+C), and DIR data (pre- or post-contrast) were acquired in 22 patients with glioblastoma. Contrast-to-noise (CNR) and tumor volumes were compared between DIR and FLAIR sequences. Line profiles across regions of tumor were generated to evaluate similarities between image contrasts. Additionally, voxel-wise associations between DIR and other sequences were examined. Results suggested post-contrast DIR images were hyperintense (bright) in regions spatially similar those having FLAIR hyperintensity and hypointense (dark) in regions with contrast-enhancement or elevated rCBV due to the high sensitivity of 3D turbo spin echo sequences to susceptibility differences between different tissues. DIR tumor volumes were statistically smaller than tumor volumes as defined by FLAIR (Paired t test, P = 0.0084), averaging a difference of approximately 14 mL or 24 %. DIR images had approximately 1.5× higher lesion CNR compared with FLAIR images (Paired t test, P = 0.0048). Line profiles across tumor regions and scatter plots of voxel-wise coherence between different contrasts confirmed a positive correlation between DIR and FLAIR signal intensity and a negative correlation between DIR and both post-contrast T1-weighted image signal intensity and rCBV. Additional discrepancies between FLAIR and DIR abnormal regions were also observed, together suggesting DIR may provide additional information beyond that of FLAIR.
PET Parametric Response Mapping for Clinical Monitoring and Treatment Response Evaluation in Brain Tumors.
Source:PET clinics
Authors:Ellingson BM; Chen W; Harris RJ; Pope WB; Lai A; Nghiemphu PL; Czernin J; Phelps ME; Cloughesy TF;
Abstract:PET parametric response maps (PRMs) are a provocative new molecular imaging technique for quantifying brain tumor response to therapy in individual patients. By aligning sequential PET scans over time using anatomic MR imaging information, the voxel-wise change in radiotracer uptake can be quantified and visualized. PET PRMs can be performed before and after a particular therapy to test whether the tumor is responding favorably, or performed relative to a distant time point to monitor changes through the course of a treatment. This article focuses on many of the technical details involved in generating, visualizing, and quantifying PET PRMs, and practical applications and example case studies.
PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Iwanami A; Gini B; Zanca C; Matsutani T; Assuncao A; Nael A; Dang J; Yang H; Zhu S; Kohyama J; Kitabayashi I; Cavenee WK; Cloughesy TF; Furnari FB; Nakamura M; Toyama Y; Okano H; Mischel PS;
Abstract:Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it.
Probabilistic radiographic atlas of glioblastoma phenotypes.
Source:AJNR. American journal of neuroradiology
Authors:Ellingson BM; Lai A; Harris RJ; Selfridge JM; Yong WH; Das K; Pope WB; Nghiemphu PL; Vinters HV; Liau LM; Mischel PS; Cloughesy TF;
Abstract:Radiographic atlases for specific phenotypes provide insight into overlap between prognostic variables and may help to identify niche locations for cancer cells of origin.
Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome.
Authors:Lalezari S; Chou AP; Tran A; Solis OE; Khanlou N; Chen W; Li S; Carrillo JA; Chowdhury R; Selfridge J; Sanchez DE; Wilson RW; Zurayk M; Lalezari J; Lou JJ; Ormiston L; Ancheta K; Hanna R; Miller P; Piccioni D; Ellingson BM; Buchanan C; Mischel PS; Nghiemphu PL; Green R; Wang HJ; Pope WB; Liau LM; Elashoff RM; Cloughesy TF; Yong WH; Lai A;
Abstract:Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.
Quantitative probabilistic functional diffusion mapping in newly diagnosed glioblastoma treated with radiochemotherapy.
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB;
Abstract:Results suggest that probabilistic fDMs are a more predictive biomarker in terms of 12-month PFS and 24-month OS in newly diagnosed glioblastoma, compared with traditional fDM analysis.
Reply to B. Freidlin et al.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Trippa L; Lee EQ; Wen PY; Batchelor TT; Cloughesy T; Parmigiani G; Alexander BM;
Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation.
Source:Nature genetics
Authors:Morris LG; Kaufman AM; Gong Y; Ramaswami D; Walsh LA; Turcan S; Eng S; Kannan K; Zou Y; Peng L; Banuchi VE; Paty P; Zeng Z; Vakiani E; Solit D; Singh B; Ganly I; Liau L; Cloughesy TC; Mischel PS; Mellinghoff IK; Chan TA;
Abstract:Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding ß-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings address two outstanding issues in cancer biology: the basis of Wnt activation in non-colorectal tumors and the identity of a 4q35 tumor suppressor.
Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients.
Source:Journal of immunotherapy (Hagerstown, Md. : 1997)
Authors:Prins RM; Wang X; Soto H; Young E; Lisiero DN; Fong B; Everson R; Yong WH; Lai A; Li G; Cloughesy TF; Liau LM;
Abstract:Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on 2 different DC vaccination protocols. Twenty-eight patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, whereas 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility, and correlative immune monitoring assay results were compared between patients on each trial. Because of HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, whereas 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (postvaccination/prevaccination) and overall survival (P = 0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for overall survival in these patients, whereas tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased postvaccination/prevaccination Treg ratios and decreased frequencies of activated natural killer cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients.
Standards of care for treatment of recurrent glioblastoma--are we there yet?
Authors:Weller M; Cloughesy T; Perry JR; Wick W;
Abstract:Newly diagnosed glioblastoma is now commonly treated with surgery, if feasible, or biopsy, followed by radiation plus concomitant and adjuvant temozolomide. The treatment of recurrent glioblastoma continues to be a moving target as new therapeutic principles enrich the standards of care for newly diagnosed disease. We reviewed PubMed and American Society of Clinical Oncology abstracts from January 2006 to January 2012 to identify clinical trials investigating the treatment of recurrent or progressive glioblastoma with nitrosoureas, temozolomide, bevacizumab, and/or combinations of these agents. At recurrence, a minority of patients are eligible for second surgery or reirradiation, based on appropriate patient selection. In temozolomide-pretreated patients, progression-free survival rates at 6 months of 20%-30% may be achieved either with nitrosoureas, temozolomide in various dosing regimens, or bevacizumab. Combination regimens among these agents or with other drugs have not produced evidence for superior activity but commonly produce more toxicity. More research is needed to better define patient profiles that predict benefit from the limited therapeutic options available after the current standard of care has failed.
Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation.
Authors:Li S; Chou AP; Chen W; Chen R; Deng Y; Phillips HS; Selfridge J; Zurayk M; Lou JJ; Everson RG; Wu KC; Faull KF; Cloughesy T; Liau LM; Lai A;
Abstract:Mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are found in a subset of gliomas. Among the many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most salient is that IDH1/2 mutant glioma patients demonstrate markedly improved survival compared with IDH1/2 wild-type glioma patients. To address the mechanism underlying the superior clinical outcome of IDH1/2 mutant glioma patients, we investigated whether overexpression of the IDH1(R132H) protein could affect response to therapy in the context of an isogenic glioma cell background. Stable clonal U87MG and U373MG cell lines overexpressing IDH1(WT) and IDH1(R132H) were generated, as well as U87MG cell lines overexpressing IDH2(WT) and IDH2(R172K). In vitro experiments were conducted to characterize baseline growth and migration and response to radiation and temozolomide. In addition, reactive oxygen species (ROS) levels were measured under various conditions. U87MG-IDH1(R132H) cells, U373MG-IDH1(R132H) cells, and U87MG-IDH2(R172K) cells demonstrated increased sensitivity to radiation but not to temozolomide. Radiosensitization of U87MG-IDH1(R132H) cells was accompanied by increased apoptosis and accentuated ROS generation, and this effect was abrogated by the presence of the ROS scavenger N-acetyl-cysteine. Interestingly, U87MG-IDH1(R132H) cells also displayed decreased growth at higher cell density and in soft agar, as well as decreased migration. Overexpression of IDH1(R132H) and IDH2(R172K) mutant protein in glioblastoma cells resulted in increased radiation sensitivity and altered ROS metabolism and suppression of growth and migration in vitro. These findings provide insight into possible mechanisms contributing to the improved outcomes observed in patients with IDH1/2 mutant gliomas.
Imaging biomarkers for antiangiogenic therapy in malignant gliomas.
Source:CNS oncology
Authors:Leu K; Pope WB; Cloughesy TF; Lai A; Nghiemphu PL; Chen W; Liau LM; Ellingson BM;
Abstract:The discovery that malignant gliomas produce an excessive amount of VEGF, a key mediator of angiogenesis, has heightened interest in developing drugs that block angiogenic pathways. These antiangiogenic drugs tend to decrease vascular permeability, thereby diminishing tumor contrast enhancement independent of anti-tumor effects. This has made the determination of tumor response difficult, since contrast enhancement on post-contrast T1-weighted images is standard for assessing therapy effectiveness. In light of these unique challenges in assessing antiangiogenic therapy, new biomarkers have been proposed, based on advanced magnetic resonance techniques and PET. This article outlines the challenges associated with the evaluation of antiangiogenic therapy in malignant gliomas and describes how new imaging biomarkers can be used to better predict response.
Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02.
Authors:Lee EQ; Kuhn J; Lamborn KR; Abrey L; DeAngelis LM; Lieberman F; Robins HI; Chang SM; Yung WK; Drappatz J; Mehta MP; Levin VA; Aldape K; Dancey JE; Wright JJ; Prados MD; Cloughesy TF; Gilbert MR; Wen PY;
Abstract:The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-ß, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation.
Authors:Lazovic J; Soto H; Piccioni D; Lou JR; Li S; Mirsadraei L; Yong W; Prins R; Liau LM; Ellingson BM; Cloughesy TF; Lai A; Pope WB;
Abstract:The arginine 132 (R132) mutation of isocitrate dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.
Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04-03.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Lee EQ; Puduvalli VK; Reid JM; Kuhn JG; Lamborn KR; Cloughesy TF; Chang SM; Drappatz J; Yung WK; Gilbert MR; Robins HI; Lieberman FS; Lassman AB; McGovern RM; Xu J; Desideri S; Ye X; Ames MM; Espinoza-Delgado I; Prados MD; Wen PY;
Abstract:Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.
A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas.
Source:Journal of neuro-oncology
Authors:Nghiemphu PL; Lai A; Green RM; Reardon DA; Cloughesy T;
Abstract:In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib, which was given alone for the first 7 days of treatments, then in combination with once daily sirolimus. Sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials.
Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas.
Source:Journal of the National Cancer Institute
Authors:Chou AP; Chowdhury R; Li S; Chen W; Kim AJ; Piccioni DE; Selfridge JM; Mody RR; Chang S; Lalezari S; Lin J; Sanchez DE; Wilson RW; Garrett MC; Harry B; Mottahedeh J; Nghiemphu PL; Kornblum HI; Mischel PS; Prins RM; Yong WH; Cloughesy T; Nelson SF; Liau LM; Lai A;
Abstract:RBP1 promoter hypermethylation is found in nearly all IDH1 and IDH2 mutant gliomas and is associated with improved patient survival. Because RBP1 is involved in retinoic acid synthesis, our results suggest that dysregulation of retinoic acid metabolism may contribute to glioma formation along the IDH1/IDH2-mutant pathway.
Persistent diffusion-restricted lesions in bevacizumab-treated malignant gliomas are associated with improved survival compared with matched controls.
Source:AJNR. American journal of neuroradiology
Authors:Mong S; Ellingson BM; Nghiemphu PL; Kim HJ; Mirsadraei L; Lai A; Yong W; Zaw TM; Cloughesy TF; Pope WB;
Abstract:Restricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor.
Bayesian adaptive randomized trial design for patients with recurrent glioblastoma.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Trippa L; Lee EQ; Wen PY; Batchelor TT; Cloughesy T; Parmigiani G; Alexander BM;
Abstract:Given the desire for control arms in phase II trials, an increasing number of experimental therapeutics, and a relatively short time for events, Bayesian AR designs are attractive for clinical trials in glioblastoma.
Glioblastoma therapy in the elderly: one age does not fit all.
Source:The Lancet. Oncology
Authors:Nghiemphu PL; Cloughesy T;
18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab.
Authors:Harris RJ; Cloughesy TF; Pope WB; Nghiemphu PL; Lai A; Zaw T; Czernin J; Phelps ME; Chen W; Ellingson BM;
Abstract:The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, (18)F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab.
Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma.
Source:AJNR. American journal of neuroradiology
Authors:Carrillo JA; Lai A; Nghiemphu PL; Kim HJ; Phillips HS; Kharbanda S; Moftakhar P; Lalaezari S; Yong W; Ellingson BM; Cloughesy TF; Pope WB;
Abstract:Imaging features are potentially predictive of IDH1 mutational status but were poorly correlated with MGMT promoter methylation. Edema stratifies survival in MGMT promoter methylated but not in unmethylated tumors; patients with methylated tumors with little or no edema have particularly long survival.
Bevacizumab as first-line therapy for glioblastoma.
Source:Future oncology (London, England)
Authors:Piccioni D; Lai A; Nghiemphu P; Cloughesy T;
Abstract:Bevacizumab is a monoclonal antibody that binds and neutralizes VEGF. Bevacizumab is currently indicated as monotherapy for recurrent glioblastoma. Recent data from Phase II trials of bevacizumab as first-line therapy for glioblastoma have been promising, and have led to two Phase III trials evaluating the use of bevacizumab as first-line therapy when combined with radiation and temozolomide. Potential complications relating to interpretation of the results of these Phase III studies include the crossover use of bevacizumab upon recurrence in the placebo arm. Recently published single-arm evaluations of adding bevacizumab to standard first-line therapy in glioblastoma multiforme have shown an improvement in progression-free survival and overall survival when compared with historical controls obtained prior to widespread use of bevacizumab in recurrent glioblastoma multiforme. When these data are compared with more contemporary studies from the bevacizumab era, the improvement in progression-free survival seems to be maintained but the impact on overall survival with first-line bevacizumab therapy seems less clear. Bevacizumab therapy alters the imaging characteristics of glioblastoma, and new criteria have been established to assess treatment response and progression in the setting of widespread bevacizumab use.
Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study.
Source:Journal of neuro-oncology
Authors:Pope WB; Qiao XJ; Kim HJ; Lai A; Nghiemphu P; Xue X; Ellingson BM; Schiff D; Aregawi D; Cha S; Puduvalli VK; Wu J; Yung WK; Young GS; Vredenburgh J; Barboriak D; Abrey LE; Mikkelsen T; Jain R; Paleologos NA; Rn PL; Prados M; Goldin J; Wen PY; Cloughesy T;
Abstract:We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.
Source:Cancer chemotherapy and pharmacology
Authors:Reardon DA; Conrad CA; Cloughesy T; Prados MD; Friedman HS; Aldape KD; Mischel P; Xia J; DiLea C; Huang J; Mietlowski W; Dugan M; Chen W; Yung WK;
Abstract:Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.
Initial treatment patterns over time for anaplastic oligodendroglial tumors.
Authors:Panageas KS; Iwamoto FM; Cloughesy TF; Aldape KD; Rivera AL; Eichler AF; Louis DN; Paleologos NA; Fisher BJ; Ashby LS; Cairncross JG; Roldán Urgoiti GB; Wen PY; Ligon KL; Schiff D; Robins HI; Rocque BG; Chamberlain MC; Mason WP; Weaver SA; Green RM; Kamar FG; Abrey LE; Deangelis LM; Jhanwar SC; Rosenblum MK; Lassman AB;
Abstract:Anaplastic oligodendroglial tumors are rare neoplasms with no standard approach to treatment. We sought to determine patterns of treatment delivered over time and identify clinical correlates of specific strategies using an international retrospective cohort of 1013 patients diagnosed from 1981-2007. Prior to 1990, most patients received radiotherapy (RT) alone as initial postoperative treatment. After 1990, approximately 50% of patients received both RT and chemotherapy (CT) sequentially and/or concurrently. Treatment with RT alone became significantly less common (67% in 1980-1984 vs 5% in 2005-2007, P < .0001). CT alone was more frequently administered in later years (0% in 1980-1984 vs 38% in 2005-2007; P < .0001), especially in patients with 1p19q codeleted tumors (57% of codeleted vs 4% with no deletion in 2005-2007; P < .0001). Temozolomide replaced the combination of procarbazine, lomustine, and vincristine (PCV) among patients who received CT alone or with RT (87% vs 2% in 2005-2007). In the most recent time period, patients with 1p19q codeleted tumors were significantly more likely to receive CT alone (with temozolomide), whereas RT with temozolomide was a significantly more common treatment strategy than either CT or RT alone in cases with no deletion (P < .0001). In a multivariate polytomous logistic regression model, the following were significantly associated with type of treatment delivered: date (5-year interval) of diagnosis (P < .0001), 1p19q codeletion (P < .0001), pure anaplastic oligodendroglioma histology (P < .01), and frontal lobe predominance (P < .05). Limited level 1 evidence is currently available to guide treatment decisions, and ongoing phase III trials will be critical to understanding the optimal therapy.
Comparison between intensity normalization techniques for dynamic susceptibility contrast (DSC)-MRI estimates of cerebral blood volume (CBV) in human gliomas.
Source:Journal of magnetic resonance imaging : JMRI
Authors:Ellingson BM; Zaw T; Cloughesy TF; Naeini KM; Lalezari S; Mong S; Lai A; Nghiemphu PL; Pope WB;
Abstract:The results suggest Gaussian normalization of leakage-corrected CBV maps may be the best choice for image intensity correction for use in large-scale, multicenter clinical trials where MR scanners and protocols vary widely due to ease of implementation, lowest variability, and highest tumor to normal tissue contrast.
Differential gene expression in glioblastoma defined by ADC histogram analysis: relationship to extracellular matrix molecules and survival.
Source:AJNR. American journal of neuroradiology
Authors:Pope WB; Mirsadraei L; Lai A; Eskin A; Qiao J; Kim HJ; Ellingson B; Nghiemphu PL; Kharbanda S; Soriano RH; Nelson SF; Yong W; Phillips HS; Cloughesy TF;
Abstract:High-ADC GBMs show greater levels of ECM protein gene expression compared with low-ADC GBMs. It is unclear whether this translates to the accumulation of higher levels of the encoded proteins. However, because ECM molecules could contribute to a proinvasive phenotype, this relationship merits further investigation.
Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies.
Source:Neuropathology and applied neurobiology
Authors:Masui K; Cloughesy TF; Mischel PS;
Abstract:The classification of malignant gliomas is moving from a morphology-based guide to a system built on molecular criteria. The development of a genomic landscape for gliomas and a better understanding of its functional consequences have led to the development of internally consistent molecular classifiers. However, development of a biologically insightful classification to guide therapy is still a work in progress. Response to targeted treatments is based not only on the presence of drugable targets, but rather on the molecular circuitry of the cells. Further, tumours are heterogeneous and change and adapt in response to drugs. Therefore, the challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. In this review, we examine the potential role of MGMT methylation, IDH1/2 mutations, 1p/19q deletions, aberrant epidermal growth factor receptor and PI3K pathways, abnormal p53/Rb pathways, cancer stem-cell markers and microRNAs as prognostic and predictive molecular markers in the setting of adult high-grade gliomas and we outline the clinically relevant subtypes of glioblastoma with genomic, transcriptomic and proteomic integrated analyses. Furthermore, we describe how these advances, especially in epidermal growth factor receptor/PI3K/mTOR signalling pathway, affect our approaches towards targeted therapy, raising new challenges and identifying new leads.
Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.
Source:Cancer discovery
Authors:Vivanco I; Robins HI; Rohle D; Campos C; Grommes C; Nghiemphu PL; Kubek S; Oldrini B; Chheda MG; Yannuzzi N; Tao H; Zhu S; Iwanami A; Kuga D; Dang J; Pedraza A; Brennan CW; Heguy A; Liau LM; Lieberman F; Yung WK; Gilbert MR; Reardon DA; Drappatz J; Wen PY; Lamborn KR; Chang SM; Prados MD; Fine HA; Horvath S; Wu N; Lassman AB; DeAngelis LM; Yong WH; Kuhn JG; Mischel PS; Mehta MP; Cloughesy TF; Mellinghoff IK;
Abstract:Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.
Phase 2 trial design in neuro-oncology revisited: a report from the RANO group.
Source:The Lancet. Oncology
Authors:Galanis E; Wu W; Cloughesy T; Lamborn K; Mann B; Wen PY; Reardon DA; Wick W; Macdonald D; Armstrong TS; Weller M; Vogelbaum M; Colman H; Sargent DJ; van den Bent MJ; Gilbert M; Chang S;
Abstract:Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents--which are competing for a small patient population, in view of the low incidence of primary brain tumours--draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs--such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs--can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology.
Impact of 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine PET/CT on managing patients with brain tumors: the referring physician's perspective.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Walter F; Cloughesy T; Walter MA; Lai A; Nghiemphu P; Wagle N; Fueger B; Satyamurthy N; Phelps ME; Czernin J;
Abstract:(18)F-DOPA PET/CT changed the intended management of 41% of patients with brain tumors, and intended management changes were implemented in 75% of these. These changes suggest a potentially important clinical role of imaging amino acid transport in the management of brain tumor patients.
Functional diffusion maps (fDMs) evaluated before and after radiochemotherapy predict progression-free and overall survival in newly diagnosed glioblastoma.
Authors:Ellingson BM; Cloughesy TF; Zaw T; Lai A; Nghiemphu PL; Harris R; Lalezari S; Wagle N; Naeini KM; Carrillo J; Liau LM; Pope WB;
Abstract:Functional diffusion mapping (fDM) has shown promise as a sensitive imaging biomarker for predicting survival in initial studies consisting of a small number of patients, mixed tumor grades, and before routine use of anti-angiogenic therapy. The current study tested whether fDM performed before and after radiochemotherapy could predict progression-free and overall survival in 143 patients with newly diagnosed glioblastoma from 2007 through 2010, many treated with anti-angiogenic therapy after recurrence. Diffusion and conventional MRI scans were obtained before and 4 weeks after completion of radiotherapy and concurrent temozolomide treatment. FDM was created by coregistering pre- and posttreatment apparent diffusion coefficient (ADC) maps and then performing voxel-wise subtraction. FDMs were categorized according to the degree of change in ADC in pre- and posttreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions. The volume fraction of fDM-classified increasing ADC(+), decreasing ADC(-), and change in ADC(+/-) were tested to determine whether they were predictive of survival. Both Bonferroni-corrected univariate log-rank analysis and Cox proportional hazards modeling demonstrated that patients with decreasing ADC in a large volume fraction of pretreatment FLAIR or contrast-enhancing regions were statistically more likely to progress earlier and expire sooner than in patients with a lower volume fraction. The current study supports the hypothesis that fDM is a sensitive imaging biomarker for predicting survival in glioblastoma.
Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy.
Source:Journal of neuro-oncology
Authors:Pope WB; Prins RM; Albert Thomas M; Nagarajan R; Yen KE; Bittinger MA; Salamon N; Chou AP; Yong WH; Soto H; Wilson N; Driggers E; Jang HG; Su SM; Schenkein DP; Lai A; Cloughesy TF; Kornblum HI; Wu H; Fantin VR; Liau LM;
Abstract:Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(-)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography-mass spectrometry (LC-MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC-MS (r (2) = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r ( 2 ) = 0.59; P = 0.026). In conclusion, water-suppressed proton ((1)H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.
Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas.
Authors:Ellingson BM; Cloughesy TF; Pope WB; Zaw TM; Phillips H; Lalezari S; Nghiemphu PL; Ibrahim H; Naeini KM; Harris RJ; Lai A;
Abstract:Promoter methylation of O6-methylguanine DNA methyltransferase (MGMT) is associated with a favorable prognosis in glioblastoma multiforme (GBM) and has been hypothesized to occur early in tumor transformation of glial cells. Thus, a possible link exists between the site of malignant transformation and MGMT promoter methylation status. Using the Analysis of Differential Involvement (ADIFFI) statistical mapping technique in a total of 358 patients with GBM, we demonstrate that human de novo GBMs occur in a high frequency contiguous with the posterior subventricular zone (SVZ); MGMT promoter methylated GBMs are lateralized to the left hemisphere, while MGMT unmethylated GBMs are lateralized to the right hemisphere; and tumors near the left temporal lobe have a significantly longer overall survival compared with tumors occurring elsewhere, independent of treatment or MGMT methylation status.
Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma.
Source:Cancer chemotherapy and pharmacology
Authors:Reardon DA; Cloughesy T; Rich J; Alfred Yung WK; Yung L; DiLea C; Huang J; Dugan M; Mietlowski W; Maes A; Conrad C;
Abstract:The coadministration of AEE788 and RAD001 in glioblastoma patients caused a clinically significant thrombocytopenia and a higher-than-expected RAD001 area under the curve concentration when dosed at 200 and 5 mg/day, respectively. After a dose reduction to AEE788 (150 mg/day) and RAD001 (5 mg qod), the combination appeared to be better tolerated.
Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery.
Source:Journal of neuro-oncology
Authors:Gilbert MR; Kuhn J; Lamborn KR; Lieberman F; Wen PY; Mehta M; Cloughesy T; Lassman AB; Deangelis LM; Chang S; Prados M;
Abstract:Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the avß3 and avß5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
Quantification of edema reduction using differential quantitative T2 (DQT2) relaxometry mapping in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Lalezari S; Zaw T; Motevalibashinaeini K; Mischel PS; Pope WB;
Abstract:The purpose of the current study was to quantify the reduction in T2 signal abnormality accompanying administration of the anti-angiogenic drug bevacizumab in recurrent glioblastoma (GBM) patients using a voxel-wise differential quantitative T2 (DQT2) mapping technique. Twenty-six patients with recurrent GBM treated with bevacizumab were scanned before and 4-6 weeks after treatment on a 1.5T clinical MR scanner. Quantitative T2 maps were created from proton density and T2-weighted images acquired using a standard multi-echo fast-spin echo sequence. T2 maps after treatment were co-registered with T2 maps prior to treatment in the same patient, and then voxel-wise subtraction was performed to create DQT2 maps for each patient. Results suggest DQT2 maps allow visualization and quantification of voxel-wise T2 changes resulting from anti-VEGF therapy. Results demonstrated a significant decrease in T2 within pre-treatment T2 abnormal regions (mean reduction = 49.4 ms at 1.5T) following anti-VEGF treatment (Wilcoxon signed rank test, P < 0.0001). An elevated residual, post-treatment, median T2 was predictive of both progression-free (Log-rank, P = 0.0074) and overall survival (Log-rank, P = 0.0393).
Nonlinear registration of diffusion-weighted images improves clinical sensitivity of functional diffusion maps in recurrent glioblastoma treated with bevacizumab.
Source:Magnetic resonance in medicine
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Pope WB;
Abstract:Diffusion-weighted imaging estimates of apparent diffusion coefficient (ADC) have shown sensitivity to brain tumor cellularity as well as response to therapy. Functional diffusion maps (fDMs) exploit these principles by examining voxelwise changes in ADC within the same patient over time. Currently, the fDM technique involves linear image registration of ADC maps from subsequent follow-up times to pretreatment ADC maps; however, misregistration of ADC maps due to geometric distortions as well as mass effect from growing tumor can confound fDM measurements. In this study, we compare the use of a nonlinear registration scheme to the current linear fDM technique in 70 patients with recurrent glioblastoma multiforme treated with bevacizumab. Results suggest that nonlinear registration of pretreatment ADC maps to post-treatment ADC maps improves the clinical predictability, sensitivity, and specificity of fDMs for both progression-free and overall survival.
3'-deoxy-3'-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Schwarzenberg J; Czernin J; Cloughesy TF; Ellingson BM; Pope WB; Geist C; Dahlbom M; Silverman DH; Satyamurthy N; Phelps ME; Chen W;
Abstract:Changes in tumor (18)F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. (18)F-FLT PET seems to be more predictive than MRI for early treatment response.
The impact of recent data on the optimization of standards of care in newly diagnosed glioblastoma.
Source:Seminars in oncology
Authors:Cloughesy T;
Abstract:Glioblastoma is an aggressive form of brain cancer with a poor long-term prognosis. Treatment regimens for newly diagnosed disease range from surgical resection alone to surgery followed by radiotherapy with concurrent and adjuvant chemotherapy. Ongoing investigations are focused on optimization of chemotherapy by improving dosing and duration schedules and utilization of biomarkers for patient selection. Our understanding of glioblastoma tumor biology, the role of molecular signaling pathways, cellular repair mechanisms, and angiogenesis has increased greatly over the past few years, leading to the investigation of a variety of targeted therapies. In addition, advances in radiographic assessment have significantly impacted not only improvement in diagnosis, but interpretation of response to therapy. In order to effectively evaluate the clinical utility of new agents, as well as incorporate advances in radiographic assessment, changes to current clinical trial design need to be considered. This article reviews the care for newly diagnosed glioblastoma, as well as how recent findings might be incorporated into patient care.
Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
Source:Molecular cancer research : MCR
Authors:Liu Y; Ye F; Yamada K; Tso JL; Zhang Y; Nguyen DH; Dong Q; Soto H; Choe J; Dembo A; Wheeler H; Eskin A; Schmid I; Yong WH; Mischel PS; Cloughesy TF; Kornblum HI; Nelson SF; Liau LM; Tso CL;
Abstract:Glioblastoma stem cells (GSC) express both radial glial cell and neural crest cell (NCC)-associated genes. We report that endothelin 3 (EDN3), an essential mitogen for NCC development and migration, is highly produced by GSCs. Serum-induced proliferative differentiation rapidly decreased EDN3 production and downregulated the expression of stemness-associated genes, and reciprocally, two glioblastoma markers, EDN1 and YKL-40 transcripts, were induced. Correspondingly, patient glioblastoma tissues express low levels of EDN3 mRNA and high levels of EDN1 and YKL-40 mRNA. Blocking EDN3/EDN receptor B (EDNRB) signaling by an EDNRB antagonist (BQ788), or EDN3 RNA interference (siRNA), leads to cell apoptosis and functional impairment of tumor sphere formation and cell spreading/migration in culture and loss of tumorigenic capacity in animals. Using exogenous EDN3 as the sole mitogen in culture does not support GSC propagation, but it can rescue GSCs from undergoing cell apoptosis. Molecular analysis by gene expression profiling revealed that most genes downregulated by EDN3/EDNRB blockade were those involved in cytoskeleton organization, pause of growth and differentiation, and DNA damage response, implicating the involvement of EDN3/EDNRB signaling in maintaining GSC migration, undifferentiation, and survival. These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSCs. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence.
Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Lai A; Kharbanda S; Pope WB; Tran A; Solis OE; Peale F; Forrest WF; Pujara K; Carrillo JA; Pandita A; Ellingson BM; Bowers CW; Soriano RH; Schmidt NO; Mohan S; Yong WH; Seshagiri S; Modrusan Z; Jiang Z; Aldape KD; Mischel PS; Liau LM; Escovedo CJ; Chen W; Nghiemphu PL; James CD; Prados MD; Westphal M; Lamszus K; Cloughesy T; Phillips HS;
Abstract:Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.
A phase I trial of tipifarnib with radiation therapy, with and without temozolomide, for patients with newly diagnosed glioblastoma.
Source:International journal of radiation oncology, biology, physics
Authors:Nghiemphu PL; Wen PY; Lamborn KR; Drappatz J; Robins HI; Fink K; Malkin MG; Lieberman FS; DeAngelis LM; Torres-Trejo A; Chang SM; Abrey L; Fine HA; Demopoulos A; Lassman AB; Kesari S; Mehta MP; Prados MD; Cloughesy TF;
Abstract:Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.
Oncogenic EGFR signaling activates an mTORC2-NF-?B pathway that promotes chemotherapy resistance.
Source:Cancer discovery
Authors:Tanaka K; Babic I; Nathanson D; Akhavan D; Guo D; Gini B; Dang J; Zhu S; Yang H; De Jesus J; Amzajerdi AN; Zhang Y; Dibble CC; Dan H; Rinkenbaugh A; Yong WH; Vinters HV; Gera JF; Cavenee WK; Cloughesy TF; Manning BD; Baldwin AS; Mischel PS;
Abstract:This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-?B. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-?B. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.
Discriminant analysis of ¹8F-fluorothymidine kinetic parameters to predict survival in patients with recurrent high-grade glioma.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Wardak M; Schiepers C; Dahlbom M; Cloughesy T; Chen W; Satyamurthy N; Czernin J; Phelps ME; Huang SC;
Abstract:Discriminant analysis using changes in ¹8F-FLT kinetic parameters early during treatment seems to be a powerful method for evaluating the efficacy of therapeutic regimens.
Graded functional diffusion map-defined characteristics of apparent diffusion coefficients predict overall survival in recurrent glioblastoma treated with bevacizumab.
Authors:Ellingson BM; Cloughesy TF; Lai A; Mischel PS; Nghiemphu PL; Lalezari S; Schmainda KM; Pope WB;
Abstract:Diffusion imaging has shown promise as a predictive and prognostic biomarker in glioma. We assessed the ability of graded functional diffusion maps (fDMs) and apparent diffusion coefficient (ADC) characteristics to predict overall survival (OS) in recurrent glioblastoma multiforme (GBM) patients treated with bevacizumab. Seventy-seven patients with recurrent GBMs were retrospectively examined. MRI scans were obtained before and approximately 6 weeks after treatment with bevacizumab. Graded fDMs were created by registering datasets to each patient's pretreatment scan and then performing voxel-wise subtraction between post- and pretreatment ADC maps. Voxels were categorized according to the degree of change in ADC within pretreatment fluid-attenuated inversion recovery (FLAIR) and contrast-enhancing regions of interest (ROIs). We found that the volume of tissue showing decreased ADC within both FLAIR and contrast-enhancing regions stratified OS (log-rank, P < .05). fDMs applied to contrast-enhancing ROIs more accurately predicted OS compared with fDMs applied to FLAIR ROIs. Graded fDMs (showing voxels with decreased ADC between 0.25 and 0.4 µm(2)/ms) were more predictive of OS than traditional (single threshold) fDMs, and the predictive ability of graded fDMs could be enhanced even further by adding the ADC characteristics from the fDM-classified voxels to the analysis (log-rank, P < .001). These results demonstrate that spatially resolved diffusion-based tumor metrics are a powerful imaging biomarker of survival in patients with recurrent GBM treated with bevacizumab.
Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?
Authors:Clarke JL; Ennis MM; Yung WK; Chang SM; Wen PY; Cloughesy TF; Deangelis LM; Robins HI; Lieberman FS; Fine HA; Abrey L; Gilbert MR; Mehta M; Kuhn JG; Aldape KD; Lamborn KR; Prados MD;
Abstract:Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or = 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.
Cell invasion, motility, and proliferation level estimate (CIMPLE) maps derived from serial diffusion MR images in recurrent glioblastoma treated with bevacizumab.
Source:Journal of neuro-oncology
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Pope WB;
Abstract:Microscopic invasion of tumor cells and undetected tumor proliferation is the primary reason for a dismal prognosis in glioblastoma patients. Identification and quantification of spatially localized brain regions undergoing high rates of cell migration and proliferation is critical for improving patient survival; however, there are currently no non-invasive imaging biomarkers for estimating proliferation and migration rates of human gliomas in vivo. To accomplish this, we developed CIMPLE (cell invasion, motility, and proliferation level estimates) image maps using serial diffusion MRI scans and a solution to a glioma growth model equation. CIMPLE represent a novel method of quantifying the level of aggressive malignant behavior. In the current pilot study, we demonstrate the utility of CIMPLE maps to predict progression free survival (PFS) and overall survival (OS) in 26 recurrent glioblastoma patients treated with bevacizumab from our Neuro-Oncology database. Voxel-wise estimates of cell proliferation rate predicted spatial regions of contrast enhancement in 35% of patients. A linear correlation was found between the mean proliferation rate and progression-free survival (PFS; P < 0.0001) as well as overall survival (OS; P = 0.0093). Similarly, the mean proliferation rate was able to stratify patients with early and late PFS as well as OS.
An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway.
Source:Cancer discovery
Authors:Guo D; Reinitz F; Youssef M; Hong C; Nathanson D; Akhavan D; Kuga D; Amzajerdi AN; Soto H; Zhu S; Babic I; Tanaka K; Dang J; Iwanami A; Gini B; Dejesus J; Lisiero DD; Huang TT; Prins RM; Wen PY; Robins HI; Prados MD; Deangelis LM; Mellinghoff IK; Mehta MP; James CD; Chakravarti A; Cloughesy TF; Tontonoz P; Mischel PS;
Abstract:Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1-dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.
It is time to include patients with brain tumors in phase I trials in oncology.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Wen PY; Schiff D; Cloughesy TF; Reardon DA; Batchelor TT; Chabner BA; Flaherty K; de Groot JF; Gilbert MR; Galanis E; Chang SM; Schwartz GK; Peereboom D; Mehta MP; Yung WK; Grossman SA; Prados MD; DeAngelis LM;
High order diffusion tensor imaging in human glioblastoma.
Source:Academic radiology
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Liau LM; Pope WB;
Abstract:These results suggest that the fourth-order diffusion tensor has the ability to add value to second-order (traditional) diffusion tensor imaging in the evaluation of glioblastoma.
Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:de Groot JF; Piao Y; Tran H; Gilbert M; Wu HK; Liu J; Bekele BN; Cloughesy T; Mehta M; Robins HI; Lassman A; DeAngelis L; Camphausen K; Chen A; Yung WK; Prados M; Wen PY; Heymach JV;
Abstract:These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:de Groot JF; Lamborn KR; Chang SM; Gilbert MR; Cloughesy TF; Aldape K; Yao J; Jackson EF; Lieberman F; Robins HI; Mehta MP; Lassman AB; Deangelis LM; Yung WK; Chen A; Prados MD; Wen PY;
Abstract:Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.
Considerations for uniform and accurate biospecimen labelling in a biorepository and research environment.
Source:Journal of clinical pathology
Authors:Kay AB; Estrada DK; Mareninov S; Silver SS; Magyar CE; Dry SM; Cloughesy TF; Yong WH;
Abstract:Correct labelling of specimens in a biorepository or research laboratory is vital, especially for translational or clinical studies linking clinical data with biospecimens. While patient privacy must be carefully protected, confusing or inadequate labelling can potentially result in the study of the wrong biospecimens with detrimental effects to the accuracy of published findings or a requirement for invaluable biospecimens to be discarded. Labelling guidelines are described in the biorepository of the University of California-Los Angeles Brain Tumour Translational Resource, and in recipient neuro-oncology laboratories to which biospecimens and derivatives are provided. This approach includes specifying identifier types, types of dates and institutions on the biospecimen labels; using multiple identifiers on each specimen when feasible; and developing a three to four-letter alphanumeric code to aid in label recognition. In addition, steps are being taken to educate recipient laboratories on best practices in labelling.
Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab.
Authors:Wefel JS; Cloughesy T; Zazzali JL; Zheng M; Prados M; Wen PY; Mikkelsen T; Schiff D; Abrey LE; Yung WK; Paleologos N; Nicholas MK; Jensen R; Vredenburgh J; Das A; Friedman HS;
Abstract:Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.
International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors.
Authors:Lassman AB; Iwamoto FM; Cloughesy TF; Aldape KD; Rivera AL; Eichler AF; Louis DN; Paleologos NA; Fisher BJ; Ashby LS; Cairncross JG; Roldán GB; Wen PY; Ligon KL; Schiff D; Robins HI; Rocque BG; Chamberlain MC; Mason WP; Weaver SA; Green RM; Kamar FG; Abrey LE; DeAngelis LM; Jhanwar SC; Rosenblum MK; Panageas KS;
Abstract:Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.
Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma.
Source:AJNR. American journal of neuroradiology
Authors:Pope WB; Lai A; Mehta R; Kim HJ; Qiao J; Young JR; Xue X; Goldin J; Brown MS; Nghiemphu PL; Tran A; Cloughesy TF;
Abstract:Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with newly diagnosed GBM. Lower ADC is associated with tumor MGMT promoter methylation, which may, in part, account for the favorable outcome associated with low ADC(L) tumors.
Rosette-forming glioneuronal tumor: a pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases.
Source:Journal of neuro-oncology
Authors:Solis OE; Mehta RI; Lai A; Mehta RI; Farchoukh LO; Green RM; Cheng JC; Natarajan S; Vinters HV; Cloughesy T; Yong WH;
Abstract:Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a mixed glio-neuronal neoplasm recently codified by the World Health Organization WHO Classification of Central Nervous System (CNS) Tumors (2007). To date, 43 cases have been described in the literature; most occurring in the fourth ventricle region. We report the fourth case involving the pineal region in a 16-year-old female with signs of increased intracranial pressure (ICP). A stereotactic biopsy of the mass was followed by a debulking procedure. Both specimens revealed classic RGNT histology. The patient had stable scans 7 months post-resection. The clinical, radiological and histopathologic features of the previously described 43 cases are reviewed along with our illustrative case. Mean age of patients was 30 ± 12.8 years with 1.9:1 female to male ratio. The most common presenting signs related to increased ICP and posterior fossa involvement, including: headache (62.8%), ataxia (39.5%) and vomiting and vertigo (both 16.3%). This tumor usually presents with cystic changes (54.5%) with focal enhancement (60.9%) and hydrocephalus (43.2%). Microcalcifications and satellite lesions were common radiographic observations. All reported cases had the classic biphasic pattern. Rosenthal fibers and eosinophilic granular bodies are each present in approximately two thirds of cases. Ki-67 labeling index is consistently low (mean (%): 1.8 ± 0.75 SD). The isocitrate dehydrogenase 1 or 2 mutation found in low grade diffuse gliomas is not identified in this RGNT case. Reported outcome is nearly uniformly excellent after complete or subtotal resection. A solitary report of recurrence after 10 years and the limited experience with this entity suggest that long term follow up is advisable.
Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab.
Authors:Ellingson BM; Cloughesy TF; Lai A; Nghiemphu PL; Mischel PS; Pope WB;
Abstract:Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS.
A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma.
Authors:Wen PY; Schiff D; Cloughesy TF; Raizer JJ; Laterra J; Smitt M; Wolf M; Oliner KS; Anderson A; Zhu M; Loh E; Reardon DA;
Abstract:This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and =3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM.
AVAglio: Phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme.
Source:Advances in therapy
Authors:Chinot OL; de La Motte Rouge T; Moore N; Zeaiter A; Das A; Phillips H; Modrusan Z; Cloughesy T;
Abstract:Despite treatment with the current standard-of-care therapies, patients with newly diagnosed glioblastoma multiforme (GBM) exhibit dismal prognoses. Bevacizumab has demonstrated activity in patients with recurrent GBM and phase 2 trials indicate that the combination of bevacizumab with standard-of-care therapy is feasible and active for patients with newly diagnosed GBM. Bevacizumab has been granted US approval for use as single-agent therapy for patients with progressive GBM following prior therapy, although it has not received approval for use in patients with GBM in Europe. Phase 3 studies have been initiated in patients with newly diagnosed GBM and are currently recruiting patients. We describe the protocol for the AVAglio phase 3 registration trial, which is designed to evaluate the efficacy and safety of combining bevacizumab with standard-of-care therapy in patients with newly diagnosed GBM.
Clinical trial end points for high-grade glioma: the evolving landscape.
Authors:Reardon DA; Galanis E; DeGroot JF; Cloughesy TF; Wefel JS; Lamborn KR; Lassman AB; Gilbert MR; Sampson JH; Wick W; Chamberlain MC; Macdonald DR; Mehta MP; Vogelbaum MA; Chang SM; Van den Bent MJ; Wen PY;
Abstract:To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.
Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab.
Authors:Pope WB; Xia Q; Paton VE; Das A; Hambleton J; Kim HJ; Huo J; Brown MS; Goldin J; Cloughesy T;
Abstract:Most patients treated with BEV or BEV+CPT-11 on BRAIN did not experience a change from baseline in radiographic characteristics of disease at the time of progression.
Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Lai A; Tran A; Nghiemphu PL; Pope WB; Solis OE; Selch M; Filka E; Yong WH; Mischel PS; Liau LM; Phuphanich S; Black K; Peak S; Green RM; Spier CE; Kolevska T; Polikoff J; Fehrenbacher L; Elashoff R; Cloughesy T;
Abstract:Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
New strategies in the molecular targeting of glioblastoma: how do you hit a moving target?
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Cloughesy TF; Mischel PS;
Abstract:Cancer is a molecularly complex, genomically unstable disease. Selection for drug-resistant mutations, activation of feedback loops, and upregulation of cross-talk pathways provide escape routes by which cancer cells maintain signal flux through critical downstream effectors to promote therapeutic resistance. Attempts to target signal transduction pathways in cancer may therefore require investigators to aim at a moving target. We need to anticipate the routes of resistance to guide the selection of drugs that will lead to durable therapeutic response. In this New Strategies article, we discuss the challenges imposed by the complexity and adaptive capacity of cancer and suggest potential new diagnostic strategies to more effectively guide targeted cancer therapy. We focus on glioblastoma, the most common malignant primary brain tumor of adults. Glioblastoma is a model for a pathway-driven, molecularly heterogeneous cancer for which new genomic insights obtained through The Cancer Genome Atlas are ripe for integration with functional biology and incorporation into new molecular diagnostic assays.
Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab.
Authors:Prados M; Cloughesy T; Samant M; Fang L; Wen PY; Mikkelsen T; Schiff D; Abrey LE; Yung WK; Paleologos N; Nicholas MK; Jensen R; Vredenburgh J; Das A; Friedman HS;
Abstract:Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR = 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR = 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.
FDA accelerated approval benefits glioblastoma.
Source:The Lancet. Oncology
Authors:Cloughesy T;
Correlation of 6-18F-fluoro-L-dopa PET uptake with proliferation and tumor grade in newly diagnosed and recurrent gliomas.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Fueger BJ; Czernin J; Cloughesy T; Silverman DH; Geist CL; Walter MA; Schiepers C; Nghiemphu P; Lai A; Phelps ME; Chen W;
Abstract:(18)F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between (18)F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, (18)F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.
Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study.
Authors:Yung WK; Vredenburgh JJ; Cloughesy TF; Nghiemphu P; Klencke B; Gilbert MR; Reardon DA; Prados MD;
Abstract:Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is active in glioblastoma. We evaluated erlotinib efficacy in patients with first-relapse glioblastoma and assessed whether response was related to EGFR amplification and/or concomitant use of enzyme-inducing antiepileptic drugs (EIAEDs) in a phase II open-label study of glioblastoma patients in first relapse. Patients took erlotinib daily until progression. Starting dose was 150 mg for patients not taking EIAEDs and 300 mg for patients taking EIAEDs. Tumors were radiographically assessed every 8 weeks. Response was evaluated by investigators and confirmed by an independent radiology facility (IRF). The primary efficacy outcome was the objective response (OR) rate, according to the modified WHO criteria. Enrollment (n = 48) was terminated after a planned interim analysis due to an insufficient number of responses. The IRF confirmed 1 complete and 2 partial responses (PRs), for an OR rate of 6.3% (95% confidence interval [CI]: 1.7-17.0). Investigators determined 1 complete response and 3 PRs, median response duration of 7.0 months, 6-month progression-free survival (PFS) of 20% (95% CI: 10.0-32.4), and median survival of 9.7 months (95% CI: 5.9-11.6). Outcomes were not related to EGFR amplification or EIAED status. Diarrhea and rash were the most common adverse events (AEs); 23% of patients experienced grade 3-4 drug-related AEs. Despite the limited number of responses, 6-month PFS and median survival reached or exceeded the previously reported values for patients undergoing chemotherapy for recurrent glioblastoma. EGFR amplification was not associated with erlotinib activity. Given the large CIs and nonrandomized nature of the study, results should be interpreted cautiously.
Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi-passageable neurosphere formation.
Source:Pediatric blood & cancer
Authors:Panosyan EH; Laks DR; Masterman-Smith M; Mottahedeh J; Yong WH; Cloughesy TF; Lazareff JA; Mischel PS; Moore TB; Kornblum HI;
Abstract:Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations.
mTOR signaling in glioblastoma: lessons learned from bench to bedside.
Authors:Akhavan D; Cloughesy TF; Mischel PS;
Abstract:Phosphatidyl-inositol-3 kinases (PI3Ks) constitute a family of intracellular lipid kinases that are frequently hyperactivated in glioblastoma. The PI3K complex links growth factor signaling with cellular proliferation, differentiation, metabolism, and survival. Mammalian target of rapamycin (mTOR) acts both as a downstream effector and upstream regulator of PI3K, thus highlighting its importance in glioblastoma. This review highlights laboratory and clinical evidence of mTOR's role in glioblastoma. Mechanisms of escape from mTOR inhibition are also discussed, as well as future clinical strategies of mTOR inhibition.
Genomic landscape of meningiomas.
Source:Brain pathology (Zurich, Switzerland)
Authors:Lee Y; Liu J; Patel S; Cloughesy T; Lai A; Farooqi H; Seligson D; Dong J; Liau L; Becker D; Mischel P; Shams S; Nelson S;
Abstract:Meningiomas are one of the most common adult brain tumors. For most patients, surgical excision is curative. However, up to 20% recur. Currently, the molecular determinants predicting recurrence and malignant transformation are lacking. We performed retrospective global genetic and genomic analysis of 85 meningioma samples of various grades. Copy number alterations were assessed by 100K single-nucleotide polymorphism arrays and correlated with gene expression, proliferation indices and clinical outcome. In addition to chromosome 22q loss, which was detected in the majority of clinical samples, chromosome 6q and 14q loss was significantly more common in recurrent tumors and was associated with anaplastic histology. Five "classes" of meningiomas were detected by gene expression analysis that correlated with copy number alterations, recurrent status and malignant histology. These classes more accurately identified recurrent tumors relative to Ki-67 index and extent of surgical resection, and highlight substantial expression heterogeneity between meningiomas. These data offer the most complete description of the genomic landscape of meningiomas, and provide broad genomic information that may be used to further stratify meningioma patients into prognostic risk groups.
Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach.
Source:Physics in medicine and biology
Authors:Rockne R; Rockhill JK; Mrugala M; Spence AM; Kalet I; Hendrickson K; Lai A; Cloughesy T; Alvord EC Jr; Swanson KR;
Abstract:Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors known as gliomas. They proliferate and invade extensively and yield short life expectancies despite aggressive treatment. Response to treatment is usually measured in terms of the survival of groups of patients treated similarly, but this statistical approach misses the subgroups that may have responded to or may have been injured by treatment. Such statistics offer scant reassurance to individual patients who have suffered through these treatments. Furthermore, current imaging-based treatment response metrics in individual patients ignore patient-specific differences in tumor growth kinetics, which have been shown to vary widely across patients even within the same histological diagnosis and, unfortunately, these metrics have shown only minimal success in predicting patient outcome. We consider nine newly diagnosed GBM patients receiving diagnostic biopsy followed by standard-of-care external beam radiation therapy (XRT). We present and apply a patient-specific, biologically based mathematical model for glioma growth that quantifies response to XRT in individual patients in vivo. The mathematical model uses net rates of proliferation and migration of malignant tumor cells to characterize the tumor's growth and invasion along with the linear-quadratic model for the response to radiation therapy. Using only routinely available pre-treatment MRIs to inform the patient-specific bio-mathematical model simulations, we find that radiation response in these patients, quantified by both clinical and model-generated measures, could have been predicted prior to treatment with high accuracy. Specifically, we find that the net proliferation rate is correlated with the radiation response parameter (r = 0.89, p = 0.0007), resulting in a predictive relationship that is tested with a leave-one-out cross-validation technique. This relationship predicts the tumor size post-therapy to within inter-observer tumor volume uncertainty. The results of this study suggest that a mathematical model can create a virtual in silico tumor with the same growth kinetics as a particular patient and can not only predict treatment response in individual patients in vivo but also provide a basis for evaluation of response in each patient to any given therapy.
Kinetics of 3'-deoxy-3'-18F-fluorothymidine during treatment monitoring of recurrent high-grade glioma.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Schiepers C; Dahlbom M; Chen W; Cloughesy T; Czernin J; Phelps ME; Huang SC;
Abstract:Overall, the relative SUV change from S1 to S3 predicted a favorable clinical outcome, whereas the SUV change from S1 to S2 did not. Long-term survivors (G3) showed a significant drop in SUV from S1 to S2 and from S1 to S3. Significant correlations were found between SUV and both the rate constant and the influx rate. The correlation coefficient between SUV(late) and influx rate was 0.91, permitting response monitoring by the measurement of (18)F-FLT uptake changes.
Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Wen PY; Macdonald DR; Reardon DA; Cloughesy TF; Sorensen AG; Galanis E; Degroot J; Wick W; Gilbert MR; Lassman AB; Tsien C; Mikkelsen T; Wong ET; Chamberlain MC; Stupp R; Lamborn KR; Vogelbaum MA; van den Bent MJ; Chang SM;
Abstract:Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.
The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Vivanco I; Rohle D; Versele M; Iwanami A; Kuga D; Oldrini B; Tanaka K; Dang J; Kubek S; Palaskas N; Hsueh T; Evans M; Mulholland D; Wolle D; Rajasekaran S; Rajasekaran A; Liau LM; Cloughesy TF; Dikic I; Brennan C; Wu H; Mischel PS; Perera T; Mellinghoff IK;
Abstract:The phosphatase and tensin homolog (PTEN) is a tumor suppressor that is inactivated in many human cancers. PTEN loss has been associated with resistance to inhibitors of the epidermal growth factor receptor (EGFR), but the molecular basis of this resistance is unclear. It is believed that unopposed phosphatidylinositol-3-kinase (PI3K) activation through multiple receptor tyrosine kinases (RTKs) can relieve PTEN-deficient cancers from their "dependence" on EGFR or any other single RTK for survival. Here we report a distinct resistance mechanism whereby PTEN inactivation specifically raises EGFR activity by impairing the ligand-induced ubiquitylation and degradation of the activated receptor through destabilization of newly formed ubiquitin ligase Cbl complexes. PTEN-associated resistance to EGFR kinase inhibitors is phenocopied by expression of dominant negative Cbl and can be overcome by more complete EGFR kinase inhibition. PTEN inactivation does not confer resistance to inhibitors of the MET or PDGFRA kinase. Our study identifies a critical role for PTEN in EGFR signal termination and suggests that more potent EGFR inhibition should overcome resistance caused by PI3K pathway activation.
Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone.
Source:Journal of neuro-oncology
Authors:Kappadakunnel M; Eskin A; Dong J; Nelson SF; Mischel PS; Liau LM; Ngheimphu P; Lai A; Cloughesy TF; Goldin J; Pope WB;
Abstract:Current therapies for glioblastoma (GBM) target bulk tumor through measures such as resection and radiotherapy. However, recent evidence suggests that targeting a subset of tumor cells, so-called cancer stem cells, may be critical for inhibiting tumor growth and relapse. The subventricular zone (SVZ), which lines the ventricles of the brain, is thought to be the origin for the majority of neural stem cells and potentially cancer stem cells. Therefore, we assessed the relationship between tumor contact with the SVZ as determined by MRI, cancer stem cell gene expression and survival in 47 patients with GBM. Using DNA microarrays, we found that genes associated with cancer stem cells were not over-expressed in tumors contacting the SVZ. Contact with the SVZ trended with shorter survival (median 358 versus 644, P = 0.066). Over-expression of CD133 (prominin-1) and maternal embryonic leucine zipper kinase (MELK) was associated with shorter survival, whereas mitogen activated protein kinase 8 (MAPK8) was associated with longer survival (P values 0.008, 0.005 and 0.002 respectively). Thus we found no evidence of a stem-cell derived genetic signature specific for GBM in contact with the SVZ, but there was a relationship between stem cell gene expression and survival. More research is required to clarify the relationship between the SVZ, cancer stem cells and survival.
AMPK: A metabolic checkpoint that regulates the growth of EGFR activated glioblastomas.
Source:Cell cycle (Georgetown, Tex.)
Authors:Guo D; Cloughesy TF; Radu CG; Mischel PS;
Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
Source:Nature genetics
Authors:Veeriah S; Taylor BS; Meng S; Fang F; Yilmaz E; Vivanco I; Janakiraman M; Schultz N; Hanrahan AJ; Pao W; Ladanyi M; Sander C; Heguy A; Holland EC; Paty PB; Mischel PS; Liau L; Cloughesy TF; Mellinghoff IK; Solit DB; Chan TA;
Abstract:Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2-q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2-q27. Thus, PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.
Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma.
Source:Journal of neuro-oncology
Authors:Norden AD; Raizer JJ; Abrey LE; Lamborn KR; Lassman AB; Chang SM; Yung WK; Gilbert MR; Fine HA; Mehta M; Deangelis LM; Cloughesy TF; Robins HI; Aldape K; Dancey J; Prados MD; Lieberman F; Wen PY;
Abstract:There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29-81) and median Karnofsky performance status (KPS) score 90 (range 60-100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.
A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy.
Authors:Raizer JJ; Abrey LE; Lassman AB; Chang SM; Lamborn KR; Kuhn JG; Yung WK; Gilbert MR; Aldape KA; Wen PY; Fine HA; Mehta M; Deangelis LM; Lieberman F; Cloughesy TF; Robins HI; Dancey J; Prados MD;
Abstract:Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT.
A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas.
Authors:Raizer JJ; Abrey LE; Lassman AB; Chang SM; Lamborn KR; Kuhn JG; Yung WK; Gilbert MR; Aldape KD; Wen PY; Fine HA; Mehta M; Deangelis LM; Lieberman F; Cloughesy TF; Robins HI; Dancey J; Prados MD;
Abstract:The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.
EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy.
Source:Science signaling
Authors:Guo D; Prins RM; Dang J; Kuga D; Iwanami A; Soto H; Lin KY; Huang TT; Akhavan D; Hock MB; Zhu S; Kofman AA; Bensinger SJ; Yong WH; Vinters HV; Horvath S; Watson AD; Kuhn JG; Robins HI; Mehta MP; Wen PY; DeAngelis LM; Prados MD; Mellinghoff IK; Cloughesy TF; Mischel PS;
Abstract:Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFR inhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1, possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of fatty acid synthesis, whereas introduction of a constitutively active mutant form of EGFR, EGFRvIII, sensitized tumor xenografts in mice to cell death, which was augmented by the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin. These results identify a previously undescribed EGFR-mediated prosurvival metabolic pathway and suggest new therapeutic approaches to treating EGFR-activated glioblastomas.
Prognostic significance of growth kinetics in newly diagnosed glioblastomas revealed by combining serial imaging with a novel biomathematical model.
Source:Cancer research
Authors:Wang CH; Rockhill JK; Mrugala M; Peacock DL; Lai A; Jusenius K; Wardlaw JM; Cloughesy T; Spence AM; Rockne R; Alvord EC Jr; Swanson KR;
Abstract:Glioblastomas are the most aggressive primary brain tumors, characterized by their rapid proliferation and diffuse infiltration of the brain tissue. Survival patterns in patients with glioblastoma have been associated with a number of clinicopathologic factors including age and neurologic status, yet a significant quantitative link to in vivo growth kinetics of each glioma has remained elusive. Exploiting a recently developed tool for quantifying glioma net proliferation and invasion rates in individual patients using routinely available magnetic resonance images (MRI), we propose to link these patient-specific kinetic rates of biological aggressiveness to prognostic significance. Using our biologically based mathematical model for glioma growth and invasion, examination of serial pretreatment MRIs of 32 glioblastoma patients allowed quantification of these rates for each patient's tumor. Survival analyses revealed that even when controlling for standard clinical parameters (e.g., age and Karnofsky performance status), these model-defined parameters quantifying biological aggressiveness (net proliferation and invasion rates) were significantly associated with prognosis. One hypothesis generated was that the ratio of the actual survival time after whatever therapies were used to the duration of survival predicted (by the model) without any therapy would provide a therapeutic response index (TRI) of the overall effectiveness of the therapies. The TRI may provide important information, not otherwise available, about the effectiveness of the treatments in individual patients. To our knowledge, this is the first report indicating that dynamic insight from routinely obtained pretreatment imaging may be quantitatively useful in characterizing the survival of individual patients with glioblastoma. Such a hybrid tool bridging mathematical modeling and clinical imaging may allow for stratifying patients for clinical studies relative to their pretreatment biological aggressiveness.
Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08).
Authors:Wen PY; Yung WK; Lamborn KR; Norden AD; Cloughesy TF; Abrey LE; Fine HA; Chang SM; Robins HI; Fink K; Deangelis LM; Mehta M; Di Tomaso E; Drappatz J; Kesari S; Ligon KL; Aldape K; Jain RK; Stiles CD; Egorin MJ; Prados MD;
Abstract:Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7-34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1-34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7-3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2,129 +/- 1,600 ng/ml and 517 +/- 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.
Bevacizumab for recurrent ependymoma.
Authors:Green RM; Cloughesy TF; Stupp R; DeAngelis LM; Woyshner EA; Ney DE; Lassman AB;
Abstract:The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.
Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Friedman HS; Prados MD; Wen PY; Mikkelsen T; Schiff D; Abrey LE; Yung WK; Paleologos N; Nicholas MK; Jensen R; Vredenburgh J; Huang J; Zheng M; Cloughesy T;
Abstract:Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
Fyn and SRC are effectors of oncogenic epidermal growth factor receptor signaling in glioblastoma patients.
Source:Cancer research
Authors:Lu KV; Zhu S; Cvrljevic A; Huang TT; Sarkaria S; Ahkavan D; Dang J; Dinca EB; Plaisier SB; Oderberg I; Lee Y; Chen Z; Caldwell JS; Xie Y; Loo JA; Seligson D; Chakravari A; Lee FY; Weinmann R; Cloughesy TF; Nelson SF; Bergers G; Graeber T; Furnari FB; James CD; Cavenee WK; Johns TG; Mischel PS;
Abstract:Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies.
The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Guo D; Hildebrandt IJ; Prins RM; Soto H; Mazzotta MM; Dang J; Czernin J; Shyy JY; Watson AD; Phelps M; Radu CG; Cloughesy TF; Mischel PS;
Abstract:The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by (18)fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.
Striking the balance between PTEN and PDK1: it all depends on the cell context.
Source:Genes & development
Authors:Iwanami A; Cloughesy TF; Mischel PS;
Abstract:The phosphatidyl-inosital-3 kinase (PI3K) signaling pathway is critical for normal brain development and function and is commonly hyperactivated in brain cancer. The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor protein and phosphate-depended kinase 1 (PDK-1) are critical regulators of this pathway. In the July 15, 2009, issue of Genes & Development, Chalhoub and colleagues (pp. 1619-1624) demonstrate PDK1-dependent and PDK1-independent effects of conditional PTEN deletion in the brain, and they identify cell type-specific differences in feedback regulation of the PI3K pathway. These studies provide important insights as to how neurons and glia may differentially regulate PI3K signaling, yielding intriguing clues about targeting PTEN-deficient brain cancers.
Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors.
Source:Journal of neuro-oncology
Authors:Liu Q; Nguyen DH; Dong Q; Shitaku P; Chung K; Liu OY; Tso JL; Liu JY; Konkankit V; Cloughesy TF; Mischel PS; Lane TF; Liau LM; Nelson SF; Tso CL;
Abstract:Glioblastoma multiforme (GBM) remains refractory to conventional therapy. CD133+ GBM cells have been recently isolated and characterized as chemo-/radio-resistant tumor-initiating cells and are hypothesized to be responsible for post-treatment recurrence. In order to explore the molecular properties of tumorigenic CD133+ GBM cells that resist treatment, we isolated CD133+ GBM cells from tumors that are recurrent and have previously received chemo-/radio-therapy. We found that the purified CD133+ GBM cells sorted from the CD133+ GBM spheres express SOX2 and CD44 and are capable of clonal self-renewal and dividing to produce fast-growing CD133- progeny, which form the major cell population within GBM spheres. Intracranial injection of purified CD133+, not CD133- GBM daughter cells, can lead to the development of YKL-40+ infiltrating tumors that display hypervascularity and pseudopalisading necrosis-like features in mouse brain. The molecular profile of purified CD133+ GBM cells revealed characteristics of neuroectoderm-like cells, expressing both radial glial and neural crest cell developmental genes, and portraying a slow-growing, non-differentiated, polarized/migratory, astrogliogenic, and chondrogenic phenotype. These data suggest that at least a subset of treated and recurrent GBM tumors may be seeded by CD133+ GBM cells with neural and mesenchymal properties. The data also imply that CD133+ GBM cells may be clinically indolent/quiescent prior to undergoing proliferative cell division (PCD) to produce CD133- GBM effector progeny. Identifying intrinsic and extrinsic cues, which promote CD133+ GBM cell self-renewal and PCD to support ongoing tumor regeneration may highlight novel therapeutic strategies to greatly diminish the recurrence rate of GBM.
18F-FDOPA PET/MRI fusion in patients with primary/recurrent gliomas: initial experience.
Source:European journal of radiology
Authors:Ledezma CJ; Chen W; Sai V; Freitas B; Cloughesy T; Czernin J; Pope W;
Abstract:(18)F-FDOPA PET/MRI fusion provides precise anatomic localization of tracer uptake and labels enhancing and non-enhancing tumor well. In a small minority of cases, (18)F-FDOPA activity may identify tumor not visible on MRI.
Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
Source:Cancer cell
Authors:McGillicuddy LT; Fromm JA; Hollstein PE; Kubek S; Beroukhim R; De Raedt T; Johnson BW; Williams SM; Nghiemphu P; Liau LM; Cloughesy TF; Mischel PS; Parret A; Seiler J; Moldenhauer G; Scheffzek K; Stemmer-Rachamimov AO; Sawyers CL; Brennan C; Messiaen L; Mellinghoff IK; Cichowski K;
Abstract:Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.
Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment.
Authors:Pope WB; Kim HJ; Huo J; Alger J; Brown MS; Gjertson D; Sai V; Young JR; Tekchandani L; Cloughesy T; Mischel PS; Lai A; Nghiemphu P; Rahmanuddin S; Goldin J;
Abstract:Pretreatment ADC histogram analysis can stratify progression-free survival in bevacizumab-treated patients with recurrent GBM.
Targeted therapy for malignant glioma patients: lessons learned and the road ahead.
Source:Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
Authors:Huang TT; Sarkaria SM; Cloughesy TF; Mischel PS;
Abstract:Molecularly targeted therapies are transforming the care of patients with malignant gliomas, including glioblastoma, the most common malignant primary brain tumor of adults. With an arsenal of small molecule inhibitors and antibodies that target key components of the signal transduction machinery that are commonly activated in gliomas, neuro-oncologists and neurosurgeons are poised to transform the care of these patients. Nonetheless, successful application of targeted therapies remains a challenge. Strategies are lacking for directing kinase inhibitor or other pathway-specific therapies to individual patients most likely to benefit. In addition, response to targeted agents is determined not only by the presence of the key mutant kinases, but also by other critical changes in the molecular circuitry of cancer cells, such as loss of key tumor suppressor proteins, the selection for kinase-resistant mutants, and the deregulation of feedback loops. Understanding these signaling networks, and studying them in patients, will be critical for developing rational combination therapies to suppress resistance for malignant glioma patients. Here we review the current status of molecular targeted therapies for malignant gliomas. We focus initially on identifying some of the insights gained to date from targeting the EGFR/PI3K/Akt/mTOR signaling pathway in patients and on how this has led toward a reconceptualization of some of the challenges and directions for targeted treatment. We describe how advances from the world of genomics have the potential to transform our approaches toward targeted therapy, and describe how a deeper understanding of the complex nature of cancer, and its adeptness at rewiring molecular circuitry to evade targeted agents, has raised new challenges and identified new leads.
The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Veeriah S; Brennan C; Meng S; Singh B; Fagin JA; Solit DB; Paty PB; Rohle D; Vivanco I; Chmielecki J; Pao W; Ladanyi M; Gerald WL; Liau L; Cloughesy TC; Mischel PS; Sander C; Taylor B; Schultz N; Major J; Heguy A; Fang F; Mellinghoff IK; Chan TA;
Abstract:Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.
Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience.
Authors:Nghiemphu PL; Liu W; Lee Y; Than T; Graham C; Lai A; Green RM; Pope WB; Liau LM; Mischel PS; Nelson SF; Elashoff R; Cloughesy TF;
Abstract:Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor.
Neurosphere formation is an independent predictor of clinical outcome in malignant glioma.
Source:Stem cells (Dayton, Ohio)
Authors:Laks DR; Masterman-Smith M; Visnyei K; Angenieux B; Orozco NM; Foran I; Yong WH; Vinters HV; Liau LM; Lazareff JA; Mischel PS; Cloughesy TF; Horvath S; Kornblum HI;
Abstract:Renewable neurosphere formation in culture is a defining characteristic of certain brain tumor initiating cells. This retrospective study was designed to assess the relationship among neurosphere formation in cultured human glioma, tumorigenic capacity, and patient clinical outcome. Tumor samples were cultured in neurosphere conditions from 32 patients with glioma, including a subpopulation of 15 patients with primary glioblastoma. A subsample of renewable neurosphere cultures was xenografted into mouse brain to determine if they were tumorigenic. Our study shows that both renewable neurosphere formation and tumorigenic capacity are significantly associated with clinical outcome measures. Renewable neurosphere formation in cultured human glioma significantly predicted an increased hazard of patient death and more rapid tumor progression. These results pertained to both the full population of glioma and the subpopulation of primary glioblastoma. Similarly, there was a significant hazard of progression for patients whose glioma had tumorigenic capacity. Multivariate analysis demonstrated that neurosphere formation remained a significant predictor of clinical outcome independent of Ki67 proliferation index. In addition, multivariate analysis of neurosphere formation, tumor grade and patient age, demonstrated that neurosphere formation was a robust, independent predictor of glioma tumor progression. Although the lengthy duration of this assay may preclude direct clinical application, these results exemplify how neurosphere culture serves as a clinically relevant model for the study of malignant glioma. Furthermore, this study suggests that the ability to propagate brain tumor stem cells in vitro is associated with clinical outcome.
The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity.
Authors:Remington M; Chtchetinin J; Ancheta K; Nghiemphu PL; Cloughesy T; Lai A;
Abstract:First-line therapy for patients with glioblastoma multiforme includes treatment with radiation and temozolomide (TMZ), an oral DNA alkylating chemotherapy. Sensitivity of glioma cells to TMZ is dependent on the level of cellular O(6)-methylguanine-DNA methyltransferase (MGMT) repair activity. Several common coding-region polymorphisms in the MGMT gene (L84F and the linked pair I143V/K178R) modify functional characteristics of MGMT and cancer risk. To determine whether these polymorphic changes influence the ability of MGMT to protect glioma cells from TMZ, we stably overexpressed enhanced green fluorescent protein (eGFP)-tagged MGMT constructs in U87MG glioma cells. We confirmed that the wild-type (WT) eGFP-MGMT protein is properly localized within the nucleus and found that L84F, I143V/K178R, and L84F/I143V/K178R eGFP-MGMT variants exhibited nuclear localization patterns indistinguishable from WT. Using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] proliferation and clonogenic survival assays, we confirmed that WT cells expressing eGFP-MGMT are resistant to TMZ treatment compared with control U87MG cells, and that each of the polymorphic eGFP-MGMT variants confers similar resistance to TMZ. However, upon exposure to O(6)-benzylguanine (O(6)-BG), a synthetic MGMT inhibitor, the L84F and L84F/I143V/K178R variants were degraded more rapidly than WT or I143V/K178R in a proteasome-dependent manner. Despite the increased O(6)-BG- stimulated protein turnover caused by the L84F alteration, cells expressing L84F eGFP-MGMT did not exhibit altered sensitivity to the combination of O(6)-BG and TMZ compared with WT cells. In conclusion, we demonstrated that the L84F polymorphic variant has altered protein turnover without modifying sensitivity of U87MG cells to TMZ or combined TMZ and O(6)-BG. These findings may provide a clue to determining the clinical significance of MGMT coding-region polymorphisms.
A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05).
Source:Journal of neuro-oncology
Authors:Butowski N; Chang SM; Junck L; DeAngelis LM; Abrey L; Fink K; Cloughesy T; Lamborn KR; Salazar AM; Prados MD;
Abstract:The combined therapy was relatively well-tolerated. This study suggests a survival advantage compared to historical studies using RT without chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea or non-temozolomide chemotherapy. Our results suggest that poly-ICLC has activity against glioblastoma and may be worth further study in combination with agents such as temozolomide.
A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas.
Source:Journal of neuro-oncology
Authors:Butowski N; Lamborn KR; Lee BL; Prados MD; Cloughesy T; DeAngelis LM; Abrey L; Fink K; Lieberman F; Mehta M; Ian Robins H; Junck L; Salazar AM; Chang SM;
Abstract:This phase II study was designed to determine the objective response rate and 6-month progression free survival of adult patients with recurrent supratentorial anaplastic glioma when treated with the immune modulator, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II study. Patients were treated with poly-ICLC alone. Patients may have had treatment for no more than two prior relapses. Treatment with poly-ICLC continued until tumor progression. Fifty five patients were enrolled in the study. Ten were ineligible after central review of pathology. Eleven percent of patients (5 of 45) had a radiographic response. Time to progression was known for 39 patients and 6 remain on treatment. The estimated 6-month progression free survival was 24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but there was no improvement in 6-month progression free survival compared to historical database nor was there an encouraging objective radiographic response rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.
Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Reardon DA; Fink KL; Mikkelsen T; Cloughesy TF; O'Neill A; Plotkin S; Glantz M; Ravin P; Raizer JJ; Rich KM; Schiff D; Shapiro WR; Burdette-Radoux S; Dropcho EJ; Wittemer SM; Nippgen J; Picard M; Nabors LB;
Abstract:Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.
A tool for improving the longitudinal imaging characterization for neuro-oncology cases.
Source:AMIA ... Annual Symposium proceedings. AMIA Symposium
Authors:Taira RK; Bui A; Hsu W; Bashyam V; Dube S; Watt E; Andrada L; El-Saden S; Cloughesy T; Kangarloo H;
Abstract:We describe the development of a prototype tool for the construction of longitudinal cases studies that can be used for teaching files, construction of clinical databases, and for patient education. The test domain is neuro-oncology. The features of the tool include: 1) natural language processing tools to assist structuring report information; 2) integration of imaging data; 3) integration of drug information; 4) target data model that includes the dimensions of space, time, existence, and causality; 5) user interface that provides three levels of information including overview, filtered summarization, and details on demand. The results of this preliminary work include a full prototype for neuro-oncology patients that allow users an efficient means for scanning a patients imaging and support data.
Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age.
Source:BMC medical genomics
Authors:Lee Y; Scheck AC; Cloughesy TF; Lai A; Dong J; Farooqi HK; Liau LM; Horvath S; Mischel PS; Nelson SF;
Abstract:The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.
Relationship between gene expression and enhancement in glioblastoma multiforme: exploratory DNA microarray analysis.
Authors:Pope WB; Chen JH; Dong J; Carlson MR; Perlina A; Cloughesy TF; Liau LM; Mischel PS; Nghiemphu P; Lai A; Nelson SF;
Abstract:The enhancement pattern divides GBM in two groups with differing prognoses. By comparing gene expression between IE and CE GBMs, it was possible to identify genes that may affect magnetic resonance imaging features of edema and enhancement, and genes whose expression levels are predictive of both improved and shortened survival.
Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability.
Source:International journal of radiation oncology, biology, physics
Authors:Lai A; Filka E; McGibbon B; Nghiemphu PL; Graham C; Yong WH; Mischel P; Liau LM; Bergsneider M; Pope W; Selch M; Cloughesy T;
Abstract:The observed toxicities were acceptable to continue enrollment toward the overall target group of 70 patients. Preliminary efficacy analysis shows encouraging mean progression-free survival. At this time data are not sufficient to encourage routine off-label use of BV combined with TMZ/RT in the setting of newly diagnosed glioblastoma without longer follow-up, enrollment of additional patients, and thorough efficacy assessment.
Neurooncology clinical trial design for targeted therapies: lessons learned from the North American Brain Tumor Consortium.
Authors:Chang SM; Lamborn KR; Kuhn JG; Yung WK; Gilbert MR; Wen PY; Fine HA; Mehta MP; DeAngelis LM; Lieberman FS; Cloughesy TF; Robins HI; Abrey LE; Prados MD;
Abstract:The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.
Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate.
Source:The New England journal of medicine
Authors:Prins RM; Cloughesy TF; Liau LM;
Time course of imaging changes of GBM during extended bevacizumab treatment.
Source:Journal of neuro-oncology
Authors:Ananthnarayan S; Bahng J; Roring J; Nghiemphu P; Lai A; Cloughesy T; Pope WB;
Abstract:Glioblastoma multiforme (GBM) are morphologically heterogeneous tumors, with varying amounts of necrosis, and edema. Previous studies have shown that treatments incorporating the VEGF antibody bevacizumab can reduce edema and tumor burden in GBM. Additionally it has been suggested that bevacizumab regimen treatment reduces the percent of tumoral necrosis. Therefore we sought to (1) determine the time course of change in necrosis, tumor, and edema volume in patients who respond to bevacizumab regimen treatment and (2) determine if GBM that progress following a response to bevacizumab regimen treatment are morphologically different from their appearance at prior tumor progression. Therefore, we retrospectively assessed tumor, necrosis, and edema volumes on MRI scans from 15 patients with recurrent GBM who responded to bevacizumab regimen treatment, and had extended (>7 month) follow-up. We found that the median time to best tumor response was 158 days (range, 16-261, SD = 63). The median best response was 72.1% reduction in tumor volume and 72.8% reduction in peritumoral edema. Most tumors (77.8%) showed resolution of necrotic areas. The relative reduction of edema and necrosis was sustained, even in patients (n = 7) who developed tumor progression. Thus the mean ratio of edema-to-tumor volume at progression on bevacizumab regimen treatment was 38.4% lower than that for the same tumors seen on progression scans following prior chemotherapy. The percentage of necrotic tumor also was diminished following progression on bevacizumab regimen treatment. These findings illustrate the time course of changes in edema and tumor volume with prolonged bevacizumab regimen treatment, and support the conclusion that the morphology of recurrent GBM following bevacizumab regimen therapy is distinct from that on other chemotherapy.
Safety of anticoagulation use and bevacizumab in patients with glioma.
Authors:Nghiemphu PL; Green RM; Pope WB; Lai A; Cloughesy TF;
Abstract:Bevacizumab in combination with chemotherapy is now being studied for the treatment of malignant gliomas. However, the risk of intracranial hemorrhage has limited its use in patients requiring full anticoagulation for venous thrombosis. To assess the safety of using anticoagulation with bevacizumab, we conducted a retrospective review of our patients who were treated with bevacizumab while receiving anticoagulation. We reviewed their medical records and imaging for signs of hemorrhage. In total, we had 21 patients who received anticoagulation and bevacizumab concurrently for a median time of 72 days. Eighteen patients had adequate anticoagulation for venous thrombosis. There were no frank lobar hemorrhages in any patient. Three patients had small, intraparenchymal hemorrhages on MRI, but only one patient actually developed symptoms due to the hemorrhage. None of these patients had residual neurological deficits from the hemorrhages. Two more patients had evidence of a minor increase in signal on noncontrast T1-weighted sequence, presumed to be petechial hemorrhages, without any clinical sequelae or progression. In contrast, seven patients who had symptomatic hemorrhages from bevacizumab were not on any anticoagulation. In this retrospective review, anticoagulation did not lead to any major hemorrhages and does not appear to be a contraindication for starting bevacizumab therapy.
Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study.
Source:Cancer chemotherapy and pharmacology
Authors:Prados MD; Yung WK; Wen PY; Junck L; Cloughesy T; Fink K; Chang S; Robins HI; Dancey J; Kuhn J;
Abstract:The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.
Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas.
Authors:Lamborn KR; Yung WK; Chang SM; Wen PY; Cloughesy TF; DeAngelis LM; Robins HI; Lieberman FS; Fine HA; Fink KL; Junck L; Abrey L; Gilbert MR; Mehta M; Kuhn JG; Aldape KD; Hibberts J; Peterson PM; Prados MD;
Abstract:The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.
Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
Source:PLoS medicine
Authors:Cloughesy TF; Yoshimoto K; Nghiemphu P; Brown K; Dang J; Zhu S; Hsueh T; Chen Y; Wang W; Youngkin D; Liau L; Martin N; Becker D; Bergsneider M; Lai A; Green R; Oglesby T; Koleto M; Trent J; Horvath S; Mischel PS; Mellinghoff IK; Sawyers CL;
Abstract: (#NCT00047073).
Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Yoshimoto K; Dang J; Zhu S; Nathanson D; Huang T; Dumont R; Seligson DB; Yong WH; Xiong Z; Rao N; Winther H; Chakravarti A; Bigner DD; Mellinghoff IK; Horvath S; Cavenee WK; Cloughesy TF; Mischel PS;
Abstract:This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies.
Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells.
Source:Journal of neuroscience research
Authors:Nakano I; Masterman-Smith M; Saigusa K; Paucar AA; Horvath S; Shoemaker L; Watanabe M; Negro A; Bajpai R; Howes A; Lelievre V; Waschek JA; Lazareff JA; Freije WA; Liau LM; Gilbertson RJ; Cloughesy TF; Geschwind DH; Nelson SF; Mischel PS; Terskikh AV; Kornblum HI;
Abstract:Emerging evidence suggests that neural stem cells and brain tumors regulate their proliferation via similar pathways. In a previous study, we demonstrated that maternal embryonic leucine zipper kinase (Melk) is highly expressed in murine neural stem cells and regulates their proliferation. Here we describe how MELK expression is correlated with pathologic grade of brain tumors, and its expression levels are significantly correlated with shorter survival, particularly in younger glioblastoma patients. In normal human astrocytes, MELK is only faintly expressed, and MELK knockdown does not significantly influence their growth, whereas Ras and Akt overexpressing astrocytes have up-regulated MELK expression, and the effect of MELK knockdown is more prominent in these transformed astrocytes. In primary cultures from human glioblastoma and medulloblastoma, MELK knockdown by siRNA results in inhibition of the proliferation and survival of these tumors. Furthermore, we show that MELK siRNA dramatically inhibits proliferation and, to some extent, survival of stem cells isolated from glioblastoma in vitro. These results demonstrate a critical role for MELK in the proliferation of brain tumors, including their stem cells, and suggest that MELK may be a compelling molecular target for treatment of high-grade brain tumors.
Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Kuhn JG; Chang SM; Wen PY; Cloughesy TF; Greenberg H; Schiff D; Conrad C; Fink KL; Robins HI; Mehta M; DeAngelis L; Raizer J; Hess K; Lamborn KR; Dancey J; Prados MD;
Abstract:Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.
Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Beroukhim R; Getz G; Nghiemphu L; Barretina J; Hsueh T; Linhart D; Vivanco I; Lee JC; Huang JH; Alexander S; Du J; Kau T; Thomas RK; Shah K; Soto H; Perner S; Prensner J; Debiasi RM; Demichelis F; Hatton C; Rubin MA; Garraway LA; Nelson SF; Liau L; Mischel PS; Cloughesy TF; Meyerson M; Golub TA; Lander ES; Mellinghoff IK; Sellers WR;
Abstract:Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
Phase I study of temozolomide and irinotecan for recurrent malignant gliomas in patients receiving enzyme-inducing antiepileptic drugs: a north american brain tumor consortium study.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Loghin ME; Prados MD; Wen P; Junck L; Lieberman F; Fine H; Fink KL; Metha M; Kuhn J; Lamborn K; Chang SM; Cloughesy T; DeAngelis LM; Robins IH; Aldape KD; Yung WK;
Abstract:The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.
Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Chen W; Delaloye S; Silverman DH; Geist C; Czernin J; Sayre J; Satyamurthy N; Pope W; Lai A; Phelps ME; Cloughesy T;
Abstract:FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
18F-FDOPA kinetics in brain tumors.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Schiepers C; Chen W; Cloughesy T; Dahlbom M; Huang SC;
Abstract:A 2-compartment model was able to describe (18)F-FDOPA kinetics in tumors in a first approximation. A 3-compartment model with corrections for metabolites and partial volume could adequately describe (18)F-FDOPA kinetics in tumors, the striatum, and the cerebellum. This model suggests that (18)F-FDOPA was transported but not trapped in tumors, unlike in the striatum. The shape of the uptake curve appeared to be related to tumor grade. After an early maximum, high-grade tumors had a steep descending branch, whereas low-grade tumors had a slowly declining curve, like that for the cerebellum but on a higher scale.
18F-fluorothymidine kinetics of malignant brain tumors.
Source:European journal of nuclear medicine and molecular imaging
Authors:Schiepers C; Chen W; Dahlbom M; Cloughesy T; Hoh CK; Huang SC;
Abstract:A three-compartment model with blood volume, metabolite, and partial volume corrections could adequately describe 18F-FLT kinetics in malignant brain tumors. Patients could be distinguished as having: (1) tumor-predominant or (2) treatment change-predominant lesions, with significantly different phosphorylation rates.
Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Carlson MR; Pope WB; Horvath S; Braunstein JG; Nghiemphu P; Tso CL; Mellinghoff I; Lai A; Liau LM; Mischel PS; Dong J; Nelson SF; Cloughesy TF;
Abstract:VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P<0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P<0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P=0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P<0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.
High-throughput oncogene mutation profiling in human cancer.
Source:Nature genetics
Authors:Thomas RK; Baker AC; Debiasi RM; Winckler W; Laframboise T; Lin WM; Wang M; Feng W; Zander T; MacConaill L; Lee JC; Nicoletti R; Hatton C; Goyette M; Girard L; Majmudar K; Ziaugra L; Wong KK; Gabriel S; Beroukhim R; Peyton M; Barretina J; Dutt A; Emery C; Greulich H; Shah K; Sasaki H; Gazdar A; Minna J; Armstrong SA; Mellinghoff IK; Hodi FS; Dranoff G; Mischel PS; Cloughesy TF; Nelson SF; Liau LM; Mertz K; Rubin MA; Moch H; Loda M; Catalona W; Fletcher J; Signoretti S; Kaye F; Anderson KC; Demetri GD; Dummer R; Wagner S; Herlyn M; Sellers WR; Meyerson M; Garraway LA;
Abstract:Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.
A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme.
Source:Journal of neuro-oncology
Authors:Groves MD; Puduvalli VK; Chang SM; Conrad CA; Gilbert MR; Tremont-Lukats IW; Liu TJ; Peterson P; Schiff D; Cloughesy TF; Wen PY; Greenberg H; Abrey LE; DeAngelis LM; Hess KR; Lamborn KR; Prados MD; Yung WK;
Abstract:This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.
PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Mellinghoff IK; Cloughesy TF; Mischel PS;
Abstract:Molecularly targeted therapies are transforming the treatment of cancer. Elucidating the dynamic signaling networks that underlie sensitivity and resistance to these inhibitors is critical for successful clinical application. There is considerable evidence to suggest that constitutively activating mutations in kinases that regulate cellular growth may result in tumor cell "addiction" and favorable response to targeted inhibition. However, there is emerging evidence to suggest that clinical response may also be determined by other changes in the molecular circuitry of cancer cells, such as loss of key tumor-suppressor proteins. Here, we will discuss resistance to epidermal growth factor receptor tyrosine kinase inhibitors in glioblastoma patients that is mediated by loss of the PTEN tumor-suppressor protein.
Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.
Source:PLoS medicine
Authors:Lee JC; Vivanco I; Beroukhim R; Huang JH; Feng WL; DeBiasi RM; Yoshimoto K; King JC; Nghiemphu P; Yuza Y; Xu Q; Greulich H; Thomas RK; Paez JG; Peck TC; Linhart DJ; Glatt KA; Getz G; Onofrio R; Ziaugra L; Levine RL; Gabriel S; Kawaguchi T; O'Neill K; Khan H; Liau LM; Nelson SF; Rao PN; Mischel P; Pieper RO; Cloughesy T; Leahy DJ; Sellers WR; Sawyers CL; Meyerson M; Mellinghoff IK;
Abstract:Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.
Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.
Source:Proceedings of the National Academy of Sciences of the United States of America
Authors:Horvath S; Zhang B; Carlson M; Lu KV; Zhu S; Felciano RM; Laurance MF; Zhao W; Qi S; Chen Z; Lee Y; Scheck AC; Liau LM; Wu H; Geschwind DH; Febbo PG; Kornblum HI; Cloughesy TF; Nelson SF; Mischel PS;
Abstract:Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n = 55 and n = 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the "metasignature" for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers.
Primary glioblastomas express mesenchymal stem-like properties.
Source:Molecular cancer research : MCR
Authors:Tso CL; Shintaku P; Chen J; Liu Q; Liu J; Chen Z; Yoshimoto K; Mischel PS; Cloughesy TF; Liau LM; Nelson SF;
Abstract:Glioblastoma is the most common and aggressive primary brain cancer. Recent isolation and characterization of brain tumor-initiating cells supports the concept that transformed neural stem cells may seed glioblastoma. We previously identified a wide array of mesenchymal tissue transcripts overexpressed in a broad set of primary glioblastoma (de novo) tumors but not in secondary glioblastoma (derived from lower-grade) tumors, low-grade astrocytomas, or normal brain tissues. Here, we extend this observation and show that a subset of primary glioblastoma tumors and their derived tumor lines express cellular and molecular markers that are associated with mesenchymal stem cells (MSC) and that glioblastoma cell cultures can be induced to differentiate into multiple mesenchymal lineage-like cell types. These findings suggest either that a subset of primary glioblastomas derive from transformed stem cells containing MSC-like properties and retain partial phenotypic aspects of a MSC nature in tumors or that glioblastomas activate a series of genes that result in mesenchymal properties of the cancer cells to effect sustained tumor growth and malignant progression.
Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Wen PY; Yung WK; Lamborn KR; Dahia PL; Wang Y; Peng B; Abrey LE; Raizer J; Cloughesy TF; Fink K; Gilbert M; Chang S; Junck L; Schiff D; Lieberman F; Fine HA; Mehta M; Robins HI; DeAngelis LM; Groves MD; Puduvalli VK; Levin V; Conrad C; Maher EA; Aldape K; Hayes M; Letvak L; Egorin MJ; Capdeville R; Kaplan R; Murgo AJ; Stiles C; Prados MD;
Abstract:Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.
Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells.
Source:Cancer research
Authors:Wang MY; Lu KV; Zhu S; Dia EQ; Vivanco I; Shackleford GM; Cavenee WK; Mellinghoff IK; Cloughesy TF; Sawyers CL; Mischel PS;
Abstract:The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTEN-deficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors.
Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Cloughesy TF; Wen PY; Robins HI; Chang SM; Groves MD; Fink KL; Junck L; Schiff D; Abrey L; Gilbert MR; Lieberman F; Kuhn J; DeAngelis LM; Mehta M; Raizer JJ; Yung WK; Aldape K; Wright J; Lamborn KR; Prados MD;
Abstract:Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.
18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Chen W; Silverman DH; Delaloye S; Czernin J; Kamdar N; Pope W; Satyamurthy N; Schiepers C; Cloughesy T;
Abstract:(18)F-FDOPA PET was more accurate than (18)F-FDG PET for imaging of low-grade tumors and evaluating recurrent tumors. (18)F-FDOPA PET may prove especially useful for imaging of recurrent low-grade tumors and for distinguishing tumor recurrence from radiation necrosis.
Using molecular information to guide brain tumor therapy.
Source:Nature clinical practice. Neurology
Authors:Mischel PS; Cloughesy T;
MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy.
Authors:Pope WB; Lai A; Nghiemphu P; Mischel P; Cloughesy TF;
Abstract:Patients with recurrent gliomas (n = 14) were treated with bevacizumab and carboplatin, cpt-11, or etoposide. Follow-up MRI scans were obtained 2 to 6 weeks after initiation of treatment. Contrast-enhancing tumor shrank in 7 patients, with reductions evident in as little as 2 weeks after initiation of therapy. Treatment seemed more effective for heterogeneously enhancing tumor compared with solidly enhancing tumor.
A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study.
Authors:Prados MD; Lamborn K; Yung WK; Jaeckle K; Robins HI; Mehta M; Fine HA; Wen PY; Cloughesy T; Chang S; Nicholas MK; Schiff D; Greenberg H; Junck L; Fink K; Hess K; Kuhn J;
Abstract:The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.
Distinct transcription profiles of primary and secondary glioblastoma subgroups.
Source:Cancer research
Authors:Tso CL; Freije WA; Day A; Chen Z; Merriman B; Perlina A; Lee Y; Dia EQ; Yoshimoto K; Mischel PS; Liau LM; Cloughesy TF; Nelson SF;
Abstract:Glioblastomas are invasive and aggressive tumors of the brain, generally considered to arise from glial cells. A subset of these cancers develops from lower-grade gliomas and can thus be clinically classified as "secondary," whereas some glioblastomas occur with no prior evidence of a lower-grade tumor and can be clinically classified as "primary." Substantial genetic differences between these groups of glioblastomas have been identified previously. We used large-scale expression analyses to identify glioblastoma-associated genes (GAG) that are associated with a more malignant phenotype via comparison with lower-grade astrocytomas. We have further defined gene expression differences that distinguish primary and secondary glioblastomas. GAGs distinct to primary or secondary tumors provided information on the heterogeneous properties and apparently distinct oncogenic mechanisms of these tumors. Secondary GAGs primarily include mitotic cell cycle components, suggesting the loss of function in prominent cell cycle regulators, whereas primary GAGs highlight genes typical of a stromal response, suggesting the importance of extracellular signaling. Immunohistochemical staining of glioblastoma tissue arrays confirmed expression differences. These data highlight that the development of gene pathway-targeted therapies may need to be specifically tailored to each subtype of glioblastoma.
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.
Source:The New England journal of medicine
Authors:Mellinghoff IK; Wang MY; Vivanco I; Haas-Kogan DA; Zhu S; Dia EQ; Lu KV; Yoshimoto K; Huang JH; Chute DJ; Riggs BL; Horvath S; Liau LM; Cavenee WK; Rao PN; Beroukhim R; Peck TC; Lee JC; Sellers WR; Stokoe D; Prados M; Cloughesy TF; Sawyers CL; Mischel PS;
Abstract:Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.
Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Cloughesy TF; Kuhn J; Robins HI; Abrey L; Wen P; Fink K; Lieberman FS; Mehta M; Chang S; Yung A; DeAngelis L; Schiff D; Junck L; Groves M; Paquette S; Wright J; Lamborn K; Sebti SM; Prados M;
Abstract:Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.
Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Liau LM; Prins RM; Kiertscher SM; Odesa SK; Kremen TJ; Giovannone AJ; Lin JW; Chute DJ; Mischel PS; Cloughesy TF; Roth MD;
Abstract:Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-beta(2) expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell-based vaccines.
Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme.
Source:Investigational new drugs
Authors:Chang SM; Wen P; Cloughesy T; Greenberg H; Schiff D; Conrad C; Fink K; Robins HI; De Angelis L; Raizer J; Hess K; Aldape K; Lamborn KR; Kuhn J; Dancey J; Prados MD;
Abstract:CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.
Differential induction of glioblastoma migration and growth by two forms of pleiotrophin.
Source:The Journal of biological chemistry
Authors:Lu KV; Jong KA; Kim GY; Singh J; Dia EQ; Yoshimoto K; Wang MY; Cloughesy TF; Nelson SF; Mischel PS;
Abstract:Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor zeta (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN (18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth.
Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG.
Source:Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Authors:Chen W; Cloughesy T; Kamdar N; Satyamurthy N; Bergsneider M; Liau L; Mischel P; Czernin J; Phelps ME; Silverman DH;
Abstract:Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.
Robustness of gene expression profiling in glioma specimen samplings and derived cell lines.
Source:Brain research. Molecular brain research
Authors:Mehrian Shai R; Reichardt JK; Ya-Hsuan H; Kremen TJ; Liau LM; Cloughesy TF; Mischel PS; Nelson SF;
Abstract:One of the most promising applications of microarrays is class distinction through gene expression profiling as a diagnostic tool. However, as there is apparent spatial heterogeneity in the morphology of cancer cells within a tumor, it is unclear if tumor sampling can be applied and yield consistent signals. In this report, we examined six brain tumors, four glioblastoma, and two oligodendroglioma biopsies. The six brain tumor tissues from two distinct different classes were dissected in four distinct areas and gene expression was profiled using microarrays. We used hierarchical clustering to compare the variability of gene expression profiles between spatially distinct biopsies of the same tumor as compared to the variability between tumors of the same histologic group. We conclude that, in general, repeat spatially distinct samples are not needed for microarray experiments and the gene expression signatures are robust across the tumor. Predominantly, variation was much greater between samples from different patients than from the multiple samplings of given tumor. Further, we compared biopsy expression profiles to the cell lines derived from those tissues. In general, the tumor cell lines vary greatly from the parental tissues and cluster more strongly with each other than the parental tissue. We select and examine the set of genes altered in expression to allow adaptation to cell culture.
EGF activates intracellular and intercellular calcium signaling by distinct pathways in tumor cells.
Source:Cancer biology & therapy
Authors:Bryant JA; Finn RS; Slamon DJ; Cloughesy TF; Charles AC;
Abstract:Epidermal growth factor (EGF)-mediated Ca2+ signaling in multiple cell lines derived from human gliomas and in the A431 epidermoid carcinoma cell line was observed using fluorescence videomicroscopy. Bath application of EGF evoked an oscillatory increase in [Ca2+]i in 4 different human glioma cell lines as well as the A431 cell line. This effect was blocked by the EGF receptor tyrosine kinase inhibitors gefitinib and erlotinib, as well as by the EGFR antibody cetuximab. In addition to this acute Ca2+ signaling response, transient exposure to EGF also potentiated subsequent Ca2+ signaling responses to other stimuli. Tumor cells transiently exposed to EGF (5 minutes), showed a sustained increase in propagation of intercellular Ca2+ waves, which have been previously shown to involve release of ATP and activation of purinergic receptors. Cells transiently exposed to EGF also showed a sustained potentiation of the Ca2+ signaling response to ATP. In contrast to the acute Ca2+ signaling response to EGF, this sustained potentiation of purinergic intercellular signaling was not blocked by gefitinib or erlotinib, while it was blocked by cetuximab. These results indicate that while the acute Ca2+ signaling response requires tyrosine kinase activation, the sustained potentiation of intercellular signaling occurs via a distinct pathway. Distinct intra- and intercellular Ca2+ signaling pathways may be mechanisms by which EGF modulates the growth and migration of tumor cells.
Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Puduvalli VK; Yung WK; Hess KR; Kuhn JG; Groves MD; Levin VA; Zwiebel J; Chang SM; Cloughesy TF; Junck L; Wen P; Lieberman F; Conrad CA; Gilbert MR; Meyers CA; Liu V; Mehta MP; Nicholas MK; Prados M;
Abstract:Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.
Brain tumor treatment: chemotherapy and other new developments.
Source:Seminars in oncology nursing
Authors:Graham CA; Cloughesy TF;
Abstract:It is essential for the oncology nurse to possess knowledge of the different types of brain tumors treated with chemotherapy, current chemotherapy regimens, new innovative therapies, and nursing management issues specific to this population.
Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs.
Source:Investigational new drugs
Authors:Chang SM; Kuhn J; Wen P; Greenberg H; Schiff D; Conrad C; Fink K; Robins HI; Cloughesy T; De Angelis L; Razier J; Hess K; Dancey J; Prados MD;
Abstract:The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.
DNA-microarray analysis of brain cancer: molecular classification for therapy.
Source:Nature reviews. Neuroscience
Authors:Mischel PS; Cloughesy TF; Nelson SF;
Abstract:Primary brain tumours are among the most lethal of all cancers, largely as a result of their lack of responsiveness to current therapy. Numerous new therapies hold great promise for the treatment of patients with brain cancer, but the main challenge is to determine which treatment is most likely to benefit an individual patient. DNA-microarray-based technologies, which allow simultaneous analysis of expression of thousands of genes, have already begun to uncover previously unrecognized patient subsets that differ in their survival. Here, we review the progress made so far in using DNA microarrays to optimize brain cancer therapy.
Gene expression profiling of gliomas strongly predicts survival.
Source:Cancer research
Authors:Freije WA; Castro-Vargas FE; Fang Z; Horvath S; Cloughesy T; Liau LM; Mischel PS; Nelson SF;
Abstract:In current clinical practice, histology-based grading of diffuse infiltrative gliomas is the best predictor of patient survival time. Yet histology provides little insight into the underlying biology of gliomas and is limited in its ability to identify and guide new molecularly targeted therapies. We have performed large-scale gene expression analysis using the Affymetrix HG U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of all histologic types to assess whether a gene expression-based, histology-independent classifier is predictive of survival and to determine whether gene expression signatures provide insight into the biology of gliomas. We found that gene expression-based grouping of tumors is a more powerful survival predictor than histologic grade or age. The poor prognosis samples could be grouped into three different poor prognosis groups, each with distinct molecular signatures. We further describe a list of 44 genes whose expression patterns reliably classify gliomas into previously unrecognized biological and prognostic groups: these genes are outstanding candidates for use in histology-independent classification of high-grade gliomas. The ability of the large scale and 44 gene set expression signatures to group tumors into strong survival groups was validated with an additional external and independent data set from another institution composed of 50 additional gliomas. This demonstrates that large-scale gene expression analysis and subset analysis of gliomas reveals unrecognized heterogeneity of tumors and is efficient at selecting prognosis-related gene expression differences which are able to be applied across institutions.
p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition.
Authors:Wang Y; Zhu S; Cloughesy TF; Liau LM; Mischel PS;
Abstract:A critical challenge in cancer research is to identify genetic lesions that sensitize patients to chemotherapy. p53, which is mutated in nearly one-third to half of glioblastomas, may be such a lesion. In this paper, we demonstrate that p53 disruption dramatically sensitizes glioblastoma cells to DNA topoisomerase I inhibitor-mediated apoptosis. Using 19 glioblastoma cell lines, including 15 low-passage ex vivo cell lines derived from patients, as well as isogenic glioblastoma cells varying in p53 status, we show that clinically relevant levels of SN-38 potently induce cell cycle arrest and temporary senescence in glioblastoma cells with wild-type p53 while causing massive apoptosis in p53-deficient cells (P<0.0002). We demonstrate that glioblastoma cells with wild-type p53 proliferate when recultured in drug-free medium, whereas p53-deficient cells do not. We also show that p16 protein expression is neither necessary nor sufficient for initiation and/or maintenance of SN-38-induced arrest/senescence. These results indicate that p53 disruption has a dramatic effect on how glioblastoma cells process topoisomerase I inhibitor-mediated DNA damage.
A prospective blinded study of the predictive value of an extreme drug resistance assay in patients receiving CPT-11 for recurrent glioma.
Source:Journal of neuro-oncology
Authors:Parker RJ; Fruehauf JP; Mehta R; Filka E; Cloughesy T;
Abstract:This adjunct to a prospective phase II blinded study of 48 patients with recurrent malignant glioma evaluated the predictive reliability of an extreme drug resistance (EDR) to identify clinical resistance to irinotecan (CPT-11), using fresh tumor biopsies obtained from recurrent patients immediately prior to their first dose of CPT-11 therapy. In vitro tumor response to SN38 (bioactive species of CPT-11 used in the EDR assay) determined prior to treatment was correlated with objective response, time to tumor progression (TTP) and survival following the administration of CPT-11. SN38 activity was tested in 19 of 29 tumors, with 15 of 18 assay results evaluable for correlation with clinical outcomes. In vitro drug resistance was classified as either extreme, intermediate (IDR), or low (LDR). TTP and survival were estimated by the Kaplan-Meier method, and compared using the Mantel-Haenszel log-rank and Fisher's exact test statistics. In vitro tumor response was bifurcated into either EDR (n = 4) or IDR/LDR (n = 11) categories for comparison with outcomes. Results correlated significantly with both TTP and survival. Median TTP for IDR/LDR cases was 3 months versus 6 weeks for EDR cases (log-rank test; p = 0.0288, hazards ratio = 3.06). A 13-week median survival for EDR cases was significantly shorter compared to 38 weeks for IDR/LDR cases (p = 0.029). Further, 100-day survival favored the IDR/LDR cases (Fisher's exact test; p = 0.008). At last follow-up, two of three survivors were patients who had tumors IDR/LDR to SN38. These prospective data support the notion that patients should avoid agents to which their tumor demonstrates EDR.
Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study.
Authors:Prados MD; Yung WK; Jaeckle KA; Robins HI; Mehta MP; Fine HA; Wen PY; Cloughesy TF; Chang SM; Nicholas MK; Schiff D; Greenberg HS; Junck L; Fink KL; Hess KR; Kuhn J;
Abstract:This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m(2) increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6 microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m(2) when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.
Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line.
Source:Laboratory investigation; a journal of technical methods and pathology
Authors:Lu KV; Jong KA; Rajasekaran AK; Cloughesy TF; Mischel PS;
Abstract:Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin alphavbeta3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.
Gene expression profiling identifies molecular subtypes of gliomas.
Authors:Shai R; Shi T; Kremen TJ; Horvath S; Liau LM; Cloughesy TF; Mischel PS; Nelson SF;
Abstract:Identification of distinct molecular subtypes is a critical challenge for cancer biology. In this study, we used Affymetrix high-density oligonucleotide arrays to identify the global gene expression signatures associated with gliomas of different types and grades. Here, we show that the global transcriptional profiles of gliomas of different types and grades are distinct from each other and from the normal brain. To determine whether our data could be used to uncover molecular subtypes without prior knowledge of pathologic type and grade, we performed K-means clustering analysis and found evidence for three clusters with the aid of multidimensional scaling plots. These clusters corresponded to glioblastomas, lower grade astrocytomas and oligodendrogliomas (P<0.00001). A predictor constructed from the 170 genes that are most differentially expressed between the subsets correctly identified the type and grade of all samples, indicating that a relatively small number of genes can be used to distinguish between these molecular subtypes. These results further define molecular subsets of gliomas which may potentially be used for patient stratification, and suggest potential targets for treatment.
Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study.
Source:Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Authors:Jaeckle KA; Hess KR; Yung WK; Greenberg H; Fine H; Schiff D; Pollack IF; Kuhn J; Fink K; Mehta M; Cloughesy T; Nicholas MK; Chang S; Prados M;
Abstract:TMZ and cRA were active, exceeding our 20% thresholds for PFS 6 success, assuming 20% improvement over our previously reported database (glioblastoma multiforme: expected, 30%; observed, 32%; anaplastic glioma: expected, 40%; observed, 50%).
Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo.
Source:Cancer research
Authors:Choe G; Horvath S; Cloughesy TF; Crosby K; Seligson D; Palotie A; Inge L; Smith BL; Sawyers CL; Mischel PS;
Abstract:Deregulated signaling through the phosphatidylinositol 3'-kinase (PI3K) pathway is common in many types of cancer, including glioblastoma. Dissecting the molecular events associated with activation of this pathway in glioblastoma patients in vivo presents an important challenge that has implications for the development and clinical testing of PI3K pathway inhibitors. Using an immunohistochemical analysis applied to a tissue microarray, we performed hierarchical clustering and multidimensional scaling, as well as univariate and multivariate analyses, to dissect the PI3K pathway in vivo. We demonstrate that loss of the tumor suppressor protein PTEN, which antagonizes PI3K pathway activation, is highly correlated with activation of the main PI3K effector Akt in vivo. We also show that Akt activation is significantly correlated with phosphorylation of mammalian target of rapamycin (mTOR), the family of forkhead transcription factors (FOXO1, FOXO3a, and FOXO4), and S6, which are thought to promote its effects. Expression of the mutant epidermal growth factor receptor vIII is also tightly correlated with phosphorylation of these effectors, demonstrating an additional route to PI3K pathway activation in glioblastomas in vivo. These results provide the first dissection of the PI3K pathway in glioblastoma in vivo and suggest an approach to stratifying patients for targeted kinase inhibitor therapy.
Two studies evaluating irinotecan treatment for recurrent malignant glioma using an every-3-week regimen.
Authors:Cloughesy TF; Filka E; Kuhn J; Nelson G; Kabbinavar F; Friedman H; Miller LL; Elfring GL;
Abstract:Two studies were performed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. In the first study, CPT-11 was administered once every 3 weeks as a 90-minute intravenous infusion at a dose of 300 mg/m(2). After 2 treatments, doses were increased to 350 mg/m(2) in those patients without Grade 3/4 toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response (PR), and 2 patients (14%) had stable disease (SD). Median survival was 24 weeks; median time to tumor progression (TTP) was 6 weeks. The primary hematologic toxicity was Grade 3/4 neutropenia, which was observed in 14% of patients. Infrequent Grade 3/4 nonhematologic toxicity was observed, possibly due to the concomitant use of anticonvulsants that might have altered pharmacokinetics. The second study evaluated the potential underdosing observed in patients who did or did not receive enzyme-inducing antiepileptic drugs (EIAED) by implementing an intrapatient dose escalation design. In this open-label study, treatment of patients with recurrent malignant glioma (rMG) was started at 300-400 mg/m(2) of CPT-11 every 3 weeks and, depending on individual safety and efficacy evaluation, escalated by steps of 100 mg/m(2) in subsequent courses. Thirty-five patients (median age, 43 years; gender, 11F and 24M; histology, 26 glioblastoma multiforme and 9 anaplastic glioma) have completed at least two cycles of chemotherapy and are evaluable for toxicity and response. Dose-limiting toxicity (DLT) was reached in 12 patients at doses ranging from 400-1700 mg/m(2). Preliminary efficacy data show that 3 patients exhibited PR and 15 patients exhibited SD. Median TTP was 2.7 months, and median survival was 8.5 months. Patients who did not receive anticonvulsants achieved higher peak concentrations, relative to dose, of the active metabolite SN-38 than did patients in the EIAED group. This study confirmed the activity of CPT-11 in malignant glioma and indicated that the maximum tolerated dose (MTD) for patients with rMG was considerably higher than expected but still possessed significant variability. A higher level of efficacy for CPT-11 may be observed if an MTD can efficiently be established for each patient.
Identification of molecular subtypes of glioblastoma by gene expression profiling.
Authors:Mischel PS; Shai R; Shi T; Horvath S; Lu KV; Choe G; Seligson D; Kremen TJ; Palotie A; Liau LM; Cloughesy TF; Nelson SF;
Abstract:Epidermal growth factor receptor (EGFR) overexpression occurs in nearly 50% of cases of glioblastoma (GBM), but its clinical and biological implications are not well understood. We have used Affymetrix high-density oligonucleotide arrays to demonstrate that EGFR-overexpressing GBMs (EGFR+) have a distinct global gene transcriptional profile. We show that the expression of 90 genes can distinguish EGFR+ from EGFR nonexpressing (EGFR-) GBMs, including a number of genes known to act as growth/survival factors for GBMs. We have also uncovered two additional novel molecular subtypes of GBMs, one of which is characterized by coordinate upregulation of contiguous genes on chromosome 12q13-15 and expression of both astrocytic and oligodendroglial genes. These results define distinct molecular subtypes of GBMs that may be important in disease stratification, and in the discovery and assessment of GBM treatment strategies.
Targeted molecular therapy of GBM.
Source:Brain pathology (Zurich, Switzerland)
Authors:Mischel PS; Cloughesy TF;
Abstract:Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype.
Source:Clinical cancer research : an official journal of the American Association for Cancer Research
Authors:Choe G; Park JK; Jouben-Steele L; Kremen TJ; Liau LM; Vinters HV; Cloughesy TF; Mischel PS;
Abstract:These results identify a novel association between MMP-9 activation and primary GBM subtype and suggest that primary GBM patients, especially those whose tumors express EGFRvIII, may benefit from anti-MMP therapy.
Novel methodology for the archiving and interactive reading of clinical magnetic resonance spectroscopic imaging.
Source:Magnetic resonance in medicine
Authors:Alger JR; Frew AJ; Cloughesy TF; Del Vecchio W; Villablanca JP; Curran JG;
Abstract:Archiving clinical magnetic resonance spectroscopic imaging (MRSI) data and presenting the data to specialists (e.g., neuroradiologists, neurosurgeons, neurologists, neuro-oncologists, and MR scientists) who work in different physical locations is a practical problem of significance. This communication describes a novel solution. The study hypothesis was that it is possible to use widely available distributed computing techniques to create a clinical MRSI user interface addressable from any personal computer with a suitable network connection. A worldwide web MRSI archive and interface system was created that permits the user to interactively view individual MRSI voxel spectra with correlation to MR images and to parametric spectroscopic images. Web browser software (i.e., Netscape and Internet Explorer) permits users in various physical locations to access centrally archived MRSI data using a variety of operating systems and client workstations. The system was used for archiving and displaying more than 1000 clinical MRSI studies performed at the authors' institution. The system also permits MRSI data to be viewed via the Internet from distant locations worldwide. The study illustrates that widely available software operating within highly distributed electronic networks can be used for archiving and interactive reading of large amounts of clinical MRSI data.
Irinotecan treatment for recurrent malignant glioma using an every-3-week regimen.
Source:American journal of clinical oncology
Authors:Cloughesy TF; Filka E; Nelson G; Kabbinavar F; Friedman H; Miller LL; Elfring GL;
Abstract:This phase II study was designed to evaluate the safety, tolerability, and efficacy of irinotecan (CPT-11) in the treatment of adults with malignant glioma. Patients with progressive or recurrent malignant gliomas were enrolled. CPT-11 was administered as a 90-minute intravenous infusion at a dose of 300 mg/m(2) once a week every 3 weeks. After 2 treatments, doses were increased to 350 mg/m(2) in those patients without grade III/IV toxicities. Dose modifications were made for toxicities. All 14 patients who enrolled (11 males and 3 females) were treated with CPT-11 and were assessable for survival, response, and toxicity. The majority of patients (86%) had prior surgery. Two patients had a confirmed partial response and 2 patients (14%) had stable disease. Median survival was 24 weeks. Median time to tumor progression was 6 weeks. The primary hematologic toxicity was grade III/IV neutropenia, which was observed in 14% of patients. Infrequent grade III/IV nonhematologic toxicity was observed, possibly because of the concomitant use of anticonvulsants, which may have altered pharmacokinetics. These results suggest that CPT-11 has activity against recurrent malignant glioma using a dosing regimen of 300 mg/m(2) every 3 weeks showing limited toxicity. The concurrent use of anticonvulsant medications may have played a role in altering pharmacokinetics and thus the maximum tolerated dose in this patient population.
A phase II trial of thymidine and carboplatin for recurrent malignant glioma: a North American Brain Tumor Consortium Study.
Authors:Robins HI; Chang SM; Prados MD; Yung WK; Hess K; Schiff D; Greenberg H; Fink K; Nicolas K; Kuhn JG; Cloughesy T; Junck L; Mehta M;
Abstract:This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.
Intraarterial chemotherapy for brain tumors by using a spatial dose fractionation algorithm and pulsatile delivery.
Authors:Gobin YP; Cloughesy TF; Chow KL; Duckwiler GR; Sayre JW; Milanese K; Viñuela F;
Abstract:Neurotoxicity of intraarterial cerebral chemotherapy can be minimized by using pulsatile injection and the described spatial dose fractionation algorithm.
Tracking tumor growth rates in patients with malignant gliomas: a test of two algorithms.
Source:AJNR. American journal of neuroradiology
Authors:Haney SM; Thompson PM; Cloughesy TF; Alger JR; Toga AW;
Abstract:The nearest-neighbor tissue segmentation algorithm provides significant power in quantifying tumor volume and in tracking growth rates of contrast-enhancing tissue in patients with GBM. The surface modeling algorithm is able to quantify tumor volume reliably as well.
Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.
Authors:Doolittle ND; Anderson CP; Bleyer WA; Cairncross JG; Cloughesy T; Eck SL; Guastadisegni P; Hall WA; Muldoon LL; Patel SJ; Peereboom D; Siegal T; Neuwelt EA;
Abstract:Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.
Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report.
Source:Neurosurgical focus
Authors:Liau LM; Black KL; Martin NA; Sykes SN; Bronstein JM; Jouben-Steele L; Mischel PS; Belldegrun A; Cloughesy TF;
Abstract:Dendritic cells (DCs) are antigen-presenting cells that play a central role in the initiation and modulation of antitumor immune responses. In this pilot study, we investigated the ability of autologous DCs pulsed ex vivo with allogeneic major histocompatibility complex class I-matched glioblastoma peptides to stimulate host antitumor immune responses when injected as a vaccine. A patient with recurrent brainstem glioblastoma multiforme (GBM) received a series of three intradermal immunizations of antigen-pulsed DCs on an outpatient basis following surgical debulking of her posterior fossa tumor. Dendritic cell vaccination was well tolerated, and no clinical signs of autoimmunity or experimental allergic encephalomyelitis were detected. She developed a measurable cellular immune response against the allogeneic glioblastoma peptides used in her vaccine preparation, as demonstrated by in vitro T-cell proliferation assays. In addition, increased T-cell infiltration was noted within the intracranial tumor site in the biopsy sample obtained following DC vaccination. An objective clinical response, however, was not evident, and this patient eventually died 21 months after her disease was diagnosed. To our knowledge, this is the first patient with brain cancer ever to be treated with DC-based immunotherapy. This case illustrates that vaccination with DCs pulsed with acid-eluted glioblastoma peptides is feasible and can induce systemic antigen-specific immunity in a patient with recurrent GBM. Additional studies are necessary to determine the optimum DC doses and antigen loading conditions that may translate into clinical effectiveness and survival benefit for patients with brain tumors. Phase I trials for malignant glioma are currently underway.
Relationships between choline magnetic resonance spectroscopy, apparent diffusion coefficient and quantitative histopathology in human glioma.
Source:Journal of neuro-oncology
Authors:Gupta RK; Cloughesy TF; Sinha U; Garakian J; Lazareff J; Rubino G; Rubino L; Becker DP; Vinters HV; Alger JR;
Abstract:This study sought to correlate quantitative presurgical proton magnetic resonance spectroscopic imaging (1H-MRSI) and diffusion imaging (DI) results with quantitative histopathological features of resected glioma tissue. The primary hypotheses were (1) glioma choline signal correlates with cell density, (2) glioma apparent diffusion coefficient (ADC) correlates inversely with cell density, (3) glioma choline signal correlates with cell proliferative index. Eighteen adult glioma patients were preoperatively imaged with 1H-MRSI and DI as part of clinically-indicated MRI evaluations. Cell density and proliferative index readings were made on surgical specimens obtained at surgery performed within 12 days of the radiologic scans. The resected tissue location was identified by comparing preoperative and postoperative MRI. The tumor to contralateral normalized choline signal ratio (nCho) and the ADC from resected tumor regions were measured from the preoperative imaging data. Counts of nuclei per high power field in 5-10 fields provided a quantitative measure of cell density. MIB-1 immunohistochemistry provided an index of the proportion of proliferating cells. There was a statistically significant inverse linear correlation between glioma ADC and cell density. There was also a statistically significant linear correlation between the glioma nCho and the cell density. The nCho measure did not significantly correlate with proliferative index. The results indicate that both ADC and spectroscopic choline measures are related to glioma cell density. Therefore they may prove useful for differentiating dense cellular neoplastic lesions from those that contain large proportions of acellular necrotic space.
Prognostic factors in recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy.
Source:AJNR. American journal of neuroradiology
Authors:Chow KL; Gobin YP; Cloughesy T; Sayre JW; Villablanca JP; Viñuela F;
Abstract:If confirmed by further studies, radiologic factors such as tumor volume and angiographic vascularity should be considered in design and stratification of future chemotherapy trials.
Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.
Source:Journal of neurosurgery
Authors:Liau LM; Black KL; Prins RM; Sykes SN; DiPatre PL; Cloughesy TF; Becker DP; Bronstein JM;
Abstract:Based on these results, dendritic antigen-presenting cells pulsed with acid-eluted peptides derived from autologous tumors represent a promising approach to the immunotherapy of established intracranial gliomas. which may serve as a basis for designing clinical trials in patients with brain tumors.
Intra-arterial Cereport (RMP-7) and carboplatin: a dose escalation study for recurrent malignant gliomas.
Authors:Cloughesy TF; Black KL; Gobin YP; Farahani K; Nelson G; Villablanca P; Kabbinavar F; Viñeula F; Wortel CH;
Abstract:Previous studies have demonstrated increased permeability in human gliomas using IA Cereport. This study demonstrates durable imaging responses using 100 mg of IA carboplatin in combination with Cereport. The drug combination in this patient population seems to be safe and acceptable, providing a novel means of antitumor dose intensification.
Inverse correlation between choline magnetic resonance spectroscopy signal intensity and the apparent diffusion coefficient in human glioma.
Source:Magnetic resonance in medicine
Authors:Gupta RK; Sinha U; Cloughesy TF; Alger JR;
Abstract:Magnetic resonance spectroscopy and diffusion magnetic resonance imaging (MRI) characteristics of human intracranial glioma were studied. Present knowledge suggests a hypothetical inverse relationship between the characteristic choline signal intensity elevation and the apparent diffusion coefficient (ADC) in glioma. Twenty cases of glioma were examined with diffusion-weighted echoplanar imaging and proton magnetic resonance spectroscopic imaging (1H-MRSI). A statistically significant inverse correlation between the choline signal intensity and the ADC was found (P = 0.0004) in radiologically defined tumor-containing regions. This study is the first in which diffusion MRI and 1H-MRSI were used to evaluate human intracranial glioma jointly. It provides insight into how to interpret choline signal intensity elevation in terms of tumor cellularity and proliferative potential when ADC images are also available.
Topographical and temporal specificity of human intraoperative optical intrinsic signals.
Authors:Cannestra AF; Black KL; Martin NA; Cloughesy T; Burton JS; Rubinstein E; Woods RP; Toga AW;
Abstract:The goal of this study was to determine the topographical and temporal specificity of neuronal and vascular responses using an intraoperative optical technique (iOIS). The face, thumb, index, and middle fingers were stimulated individually to obtain separate maps of cortical activation. Peak optical responses provided unique, non-overlapping cortical brain maps. Non-peak signals were more dispersed and produced overlapping responses from different digits. Peak iOIS responses colocalized with electrocortical stimulation mapping and evoked potentials. Temporally, we observed statistically significant specificity corresponding to sequential cortical activation during early optical signals (500-1750 ms), but later perfusion responses were non-specific. To our knowledge, this is the first report of either topographical specificity in overlapping spatial patterns, and/or temporal specificity in early perfusion profiles. These results therefore may have significant implications for other perfusion dependent functional imaging techniques.
Intra-arterial carboplatin chemotherapy for brain tumors: a dose escalation study based on cerebral blood flow.
Source:Journal of neuro-oncology
Authors:Cloughesy TF; Gobin YP; Black KL; Viñuela F; Taft F; Kadkhoda B; Kabbinavar F;
Abstract:Hemispheric blood-flow estimation allowed us to escalate the dose of intra-arterial carboplatin to twice what was previously considered safe. Responses compared favorably to previous studies. Further studies are needed to determine if this method will provide improved and durable responses.
Prolonged treatment with biologic agents for malignant glioma: a case study with high dose tamoxifen.
Source:Journal of neuro-oncology
Authors:Cloughesy TF; Woods RP; Black KL; Couldwell WT; Law RE; Hinton DR;
Abstract:Traditional study design for treatment of malignant gliomas does not allow tumor progression to be greater than 25-50 percent without terminating treatment. This design may prevent recognition of patients who benefit from the treatment either by slowed growth or delayed response. A delayed response or slowed growth may be characteristic of biologic agents being evaluated in the treatment of malignant glioma. Because of the low toxicity of certain biologic drugs, continued treatment through tumor growth can be ethically considered in study design. The effect of biologic agents on a neoplasm may include cellular differentiation, retardation of growth, cytostasis, cytocidal effects, or apoptosis. Such effects may clinically translate into a complete response, partial response, stable disease or retardation of growth with or without an eventual reduction of tumor. We present a patient with a recurrent malignant glioma who was continued on high dose tamoxifen despite radiologic documented doubling of the tumor size and who eventually showed a delayed response to this agent nine months after initiation of treatment. Strong consideration should be given to the prolonged treatment of non-toxic biologic agents in a controlled clinical trial, where agents have shown some benefit in phase one studies.
Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas.
Source:Journal of neurosurgery
Authors:Black KL; Cloughesy T; Huang SC; Gobin YP; Zhou Y; Grous J; Nelson G; Farahani K; Hoh CK; Phelps M;
Abstract:The bradykinin analog, RMP-7, was investigated for its ability to increase selectively the transport of 68Ga ethylenediamine tetraacetic acid (EDTA) into recurrent malignant gliomas in nine patients. For each patient, two position emission tomography (PET) studies (one with and one without RMP-7) were performed. For studies with RMP-7, 10 to 300 ng/kg of the compound was infused into the supraophthalmic carotid artery over 15 minutes. In each PET study, a sequence of PET scans was initiated simultaneously with an intravenous bolus of 68Ga EDTA (5-10 mCi). Arterial samples were taken to provide the input function. All PET scans were coregistered to the magnetic resonance (MR) images of the patient. Regions of interest were defined for tumor and normal tissue regions on MR images and were copied to the coregistered PET dynamic images to provide brain tissue-time activity curves. The constant (Ki) for the transport of gallium-68 from plasma to brain tissue was determined using a simple compartmental model. Intracarotid infusion of RMP-7 significantly increased transport into tumor regions with an average increase of 46 +/- 42% (mean +/- standard deviation, p < 0.05). Permeability in normal tissue regions was not significantly increased. Tumors in three of six patients treated with 300 ng/kg RMP-7 and carboplatin had at least a 50% reduction in tumor volume as measured by MR imaging. Intracarotid infusion of RMP-7 is a novel technique for selective delivery of antitumor compounds into brain tumors.
Pharmacological blood-brain barrier modification for selective drug delivery.
Source:Journal of neuro-oncology
Authors:Cloughesy TF; Black KL;
Abstract:Vasoactive agents have been identified through studies of peritumoral edema and effects on systemic capillaries. Abnormal blood-brain barrier or blood-tumor barrier can develop transient increases in permeability with the intraarterial delivery of vasoactive agents. Normal blood-brain barrier resists the effects of these compounds because of a biochemical barrier that may inactivate or become inert to vasoactive agents. Vasoactive compounds, including leukotrienes, bradykinin, and histamine appear to selectively increase permeability in abnormal brain capillaries. Intracarotid infusion of leukotrienes, bradykinin, and other vasoactive agents can increase drug delivery to diseased tissue.
Alien hand syndrome: interhemispheric motor disconnection due to a lesion in the midbody of the corpus callosum.
Authors:Geschwind DH; Iacoboni M; Mega MS; Zaidel DW; Cloughesy T; Zaidel E;
Abstract:The neuroanatomic substrate of the alien hand syndrome has remained controversial due to the noncircumscribed nature of cerebral injuries present in most cases. There have been few cases studied in which damage was restricted to portions of the body of the callosum, and most of those involved surgical callosotomy for tumors or epilepsy. We report the case of a woman with a transient alien hand syndrome caused by a stroke limited to the middle and posterior portions of the body of the corpus callosum. This case provides supportive evidence for damage to the midbody of the corpus callosum as the anatomic basis of nondominant alien hand syndrome and conforms to a model of interhemispheric motor disconnection as the essential component of this unusual behavioral syndrome. This disconnection can occur with injuries involving interhemispheric premotor and motor fibers traveling in the midportion of the callosum in individuals with left hemisphere dominance for motor activities.
Novel brainstem syndrome associated with prostate carcinoma.
Authors:Baloh RW; DeRossett SE; Cloughesy TF; Kuncl RW; Miller NR; Merrill J; Posner JB;
Abstract:Two patients successfully treated for prostatic cancer developed a progressive neurologic syndrome beginning with loss of voluntary horizontal eye movements followed by severe, persistent muscle spasms of the face, jaw, and pharynx. Both had mild gait unsteadiness, and one exhibited facial and abdominal myoclonus. Extensive diagnostic studies, including MRIs of the brainstem (with and without contrast), were normal. CSF examination showed mild pleocytosis and elevated IgG. Quantitative eye movement recordings documented selective involvement of voluntary horizontal saccades with sparing of horizontal slow eye movements. Neither patient had antineuronal antibodies in the blood. Postmortem examination revealed perivascular chronic inflammatory cells and microglial infiltration of the pons and medulla. One patient also had perivascular infiltrates in both mesial temporal lobes. Neuronal loss was localized to the pontine tegmentum, the medullary sensory nuclei, and the cerebellum. Brainstem motor nuclei were preserved. The clinical and pathologic findings suggest an autoimmune process (probably paraneoplastic) with selective damage to a subpopulation of brainstem neurons critical for horizontal eye movements and recurrent inhibition of bulbar nuclei.
Monitoring carotid test occlusions with continuous EEG and clinical examination.
Source:Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society
Authors:Cloughesy TF; Nuwer MR; Hoch D; Vinuela F; Duckwiler G; Martin N;
Abstract:We routinely monitor invasive neuroradiologic carotid balloon test occlusions with continuous polygraph and quantitative EEG along with repeated detailed clinical examinations. Four of 17 consecutive cases showed changes during carotid occlusion. In one instance, an immediate delta increase was accompanied by slurred speech and aphasia. Another showed alpha attenuation without clinical change. A third patient had significant clinical change without EEG change. Nine of the 17 cases underwent permanent therapeutic carotid occlusion as treatment of an intracerebral vascular abnormality. Seven of these nine had no EEG or clinical changes during monitoring and have had no functional abnormalities on follow-up. The patient with focal alpha attenuation had an accidental balloon detachment but has had no functional or structural neurologic abnormalities. The patient with minor regional increased delta received a permanent carotid occlusion and went on to develop clinical signs 24 h later. We believe that continuous EEG monitoring and repeated clinical examinations provide useful ways of evaluating cerebral circulation during carotid test occlusions.

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[Content Published:10/20/2017 1:44:49 PM PST]