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In this issue of Cancer Cell, Spitzer and colleagues demonstrate the role of IDH inhibitors on IDHmutant gliomas in reducing proliferation and enhancing cell differentiation toward an astrocytic-like state, thus altering neurodevelopmental pathways. Despite clinical promise, unresolved questions regarding mechanisms of action and resistance underline the need for further research for treatment optimization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Summary: This commentary urges a paradigm shift in how we approach research and drug development for glioblastoma, reimagining it as an aberrant brain-like organ, distinct from other cancers, to inspire innovative treatment strategies and interdisciplinary collaboration, addressing the minimal progress in extending glioblastoma patient survival despite years of research and investment., (©2024 American Association for Cancer Research.)

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable to xenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal + GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues., Competing Interests: Declaration of interests H-M.J. and J.L. are co-inventors on a filed patent application for the use of truncated F7 recombinant protein to treat cancer., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our glioblastoma cerebral organoid model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in other in vitro models. These analyses identified the epigenetic underpinnings of GBM cellular states and characterized dynamic chromatin changes reminiscent of early neural development that underlie GBM cell state transitions. Despite large differences between tumors, a shared cellular compartment made up of neural progenitor-like cells and outer radial glia-like cells was observed. Together, these results shed light on the transcriptional regulation program in GBM and offer novel therapeutic targets across a broad range of genetically heterogenous GBMs., Significance: Single-cell analyses elucidate the chromatin landscape and transcriptional regulation of glioblastoma cellular states and identify a radial glia-like population, providing potential targets to disrupt cell states and improve therapeutic efficacy., (©2023 American Association for Cancer Research.)

Both primary and metastatic brain tumors carry poor prognoses despite modern advances in medical therapy, radiation therapy, and surgical techniques. Gliomas, including glioblastoma (GBM), are particularly difficult to treat, and high-grade gliomas have poor outcomes. Treatment of brain tumors involves a unique set of scientific and clinical challenges, which are often not present in the treatment of systemic malignancies. With respect to scientific challenges, the anatomy and physiology of brain tumors (including the blood-brain barrier, blood-tumor barrier, and blood-cerebrospinal fluid barrier) prevent adequate drug delivery into the central nervous system. The unique nature of the immune system in the central nervous system as well as the immunosuppressive microenvironment of tumors such as GBM also create therapeutic roadblocks in the treatment of brain tumors. Tumor heterogeneity, particularly in GBM, has classically been believed to contribute to multitherapy resistance; however, recent data suggest that this may not be the case. Clinical challenges include neurologic and medical comorbidities of patients with brain tumor, as well as potential toxicity of tumor-directed treatment. Clinical trials investigating new treatment paradigms are needed, but several roadblocks exist to good and promising clinical trial availability., (Copyright © 2021. Published by Elsevier Inc.)

Although outcomes for many brain tumors, especially glioblastomas, remain poor, there have been significant advances in clinical and scientific understanding of neuro-oncologic disease. Tumor molecular profiling has become a critical component of clinical practice, allowing more accurate pathologic diagnosis and enhanced clarity of the pathogenesis of both primary and metastatic brain tumors. The development of cerebral organoids carries exciting potential to provide representative models of tumor growth and potential drug efficacy, while new radiology techniques continue to improve clinical decision making. New adaptive trial platforms have been developed to rapidly test therapies and biomarkers with good scientific rationale. Lastly, growth and development of neuro-oncology clinical care teams aim to further improve patients' outcomes and symptoms, especially at the end of life., (Copyright © 2021. Published by Elsevier Inc.)

Background and Purpose: Glioblastomas (GBMs) that involve the subventricular zone (SVZ) have a poor prognosis, possibly due to recruitment of neural stem cells. The purpose of this study was to evaluate whether SVZ involvement by lower grade gliomas (LGG), WHO grade II and III, similarly predicts poorer outcomes. We further assessed whether tumor genetics and cellularity are associated with SVZ involvement and outcomes., Methods: Forty-five consecutive LGG patients with preoperative imaging and next generation sequencing were included in this study. Regional SVZ involvement and whole tumor apparent diffusion coefficient (ADC) values, as a measure of cellularity, were assessed on magnetic resonance imaging. Progression was determined by RANO criteria. Kaplan-Meier curves and Cox regression analyses were used to determine the hazard ratios (HR) for progression and survival., Results: Frontal, parietal, temporal, and overall SVZ involvement and ADC values were not associated with progression or survival (P ≥ .05). However, occipital SVZ involvement, seen in two patients, was associated with a higher risk of tumor progression (HR = 6.6, P = .016) and death (HR = 31.5, P = .015), CDKN2A/B mutations (P = .03), and lower ADC histogram values at the 5th (P = .026) and 10th percentiles (P = .046). Isocitrate dehydrogenase, phosphatase and tensin homolog, epidermal growth factor receptor, and cyclin-dependent kinase 4 mutations were also prognostic (P ≤ .05)., Conclusions: Unlike in GBM, overall SVZ involvement was not found to strongly predict poor prognosis in LGGs. However, occipital SVZ involvement, though uncommon, was prognostic and found to be associated with CDKN2A/B mutations and tumor hypercellularity. Further investigation into these molecular mechanisms underlying occipital SVZ involvement in larger cohorts is warranted., (© 2020 American Society of Neuroimaging.)

Glioblastoma (GBM) is the most common type of malignant primary brain tumor in adults. It is a uniformly fatal disease (median overall survival 16 months) even with aggressive resection and an adjuvant temozolomide-based chemoradiation regimen. Age remains an independent risk factor for a poor prognosis. Several factors contribute to the dismal outcomes in the elderly population with GBM, including poor baseline health status, differences in underlying genomic alterations, and variability in the surgical and medical management of this subpopulation. The latter arises from a lack of adequate representation of elderly patients in clinical trials, resulting in limited data on the response of this subpopulation to standard treatment. Results from retrospective and some prospective studies have indicated that resection of only contrast-enhancing lesions and administration of hypofractionated radiotherapy in combination with temozolomide are effective strategies for optimizing survival while maintaining baseline quality of life in elderly GBM patients; however, survival remains dismal relative to that in a younger cohort. Here, the authors present historical context for the current strategies used for the multimodal management (surgical and medical) of elderly patients with GBM. Furthermore, they provide insights into elderly GBM patient-specific genomic signatures such as isocitrate dehydrogenase 1/2 (IDH1/2) wildtype status, telomerase reverse transcriptase promoter (TERTp) mutations, and somatic copy number alterations including CDK4/MDM2 coamplification, which are becoming better understood and could be utilized in a clinical trial design and patient stratification to guide the development of more effective adjuvant therapies specifically for elderly GBM patients.

Glioblastoma (GBM) remains a devastating disease with a median survival of less than two years. Current preclinical models are unable to accurately reflect the complexity of human GBM. We recently established a cerebral organoid glioma (GLICO) model to study the invasion and biology of patient-derived glioma stem cells in miniature replicas of the human brain. Through the dissemination of our detailed methodology, we aim to encourage other scientists to further build upon our existing model for studying these destructive tumors. For complete details on the use and execution of this protocol, please refer to Linkous et al. (2019)., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing financial interests.

Objectives: Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. This study aimed to evaluate the feasibility of texture analysis on preoperative conventional MRI images in predicting early malignant transformation from low- to high-grade glioma and compare its utility to histogram analysis alone., Methods: A total of 68 patients with low-grade glioma (LGG) were included in this study, 15 of which showed malignant transformation. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analyses were performed to obtain the most discriminant factor (MDF) values for both training and testing data. Receiver operating characteristic (ROC) curve analyses were performed on MDF values and 9 histogram parameters in the training data to obtain cutoff values for determining the correct rates of discrimination between two groups in the testing data., Results: The ROC analyses on MDF values resulted in an area under the curve (AUC) of 0.90 (sensitivity 85%, specificity 84%) for T2w FLAIR, 0.92 (86%, 94%) for ADC, 0.96 (97%, 84%) for T1w, and 0.82 (78%, 75%) for T1w + Gd and correctly discriminated between the two groups in 93%, 100%, 93%, and 92% of cases in testing data, respectively. In the astrocytoma subgroup, AUCs were 0.92 (88%, 83%) for T2w FLAIR and 0.90 (92%, 74%) for T1w + Gd and correctly discriminated two groups in 100% and 92% of cases. The MDF outperformed all 9 of the histogram parameters., Conclusion: Texture analysis on conventional preoperative MRI images can accurately predict early malignant transformation of LGGs, which may guide therapeutic planning., Key Points: • Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. • Texture analysis based on conventional preoperative MR images can accurately predict early malignant transformation from low- to high-grade glioma. • Texture analysis is a clinically feasible technique that may provide an alternative and effective way of determining the likelihood of early malignant transformation and help guide therapeutic decisions.

Background and Purpose: Telomerase reverse transcriptase (TERT) promoter mutations are associated with worse prognosis in glioblastoma. The purpose of this study was to evaluate whether TERT mutation status was associated with specific morphologic and quantitative imaging features., Methods: Twenty-nine patients with isocitrate dehydrogenase 1/2-wildtype glioblastoma (13 TERT-wildtype, 16 TERT-mutated), who underwent preoperative magnetic resonance (MR) imaging were included in this retrospective study. Qualitative imaging phenotypes were evaluated using the Visually Accessible Rembrandt Images (VASARIs) feature set. Histogram analysis of apparent diffusion coefficient (ADC) and dynamic contrast-enhanced MR perfusion values were performed on enhancing tumor volumes-of-interest, and differences between TERT-wildtype and TERT-mutated tumors were assessed., Results: VASARI analysis demonstrated that the majority of morphologic features were not significantly different between TERT-wildtype and TERT-mutated tumors, although a higher proportion of TERT-wildtype tumors featured nonenhancing tumor crossing midline (P = .014). TERT-mutated tumors demonstrated lower median rate constant k ep (.38 vs. .76, P = .03) and lower median volume transfer coefficient K trans (.13 vs. .31, P = .02). There was no significant difference in median plasma volume v p (P = .92) or ADC values (P = .66) between the two groups. We further found a significant interaction between median k ep and K trans and TERT status, respectively, suggesting greater risk of death with increasing blood-brain barrier dysfunction in TERT-mutated but not in TERT-wildtype tumors., Conclusion: Our study demonstrates evidence of altered permeability metrics associated with TERT mutation in glioblastoma, laying the foundation for future prospective studies assessing implications for therapeutic management and clinical outcomes., (© 2019 by the American Society of Neuroimaging.)

Objective: Both 18 F-FDG PET and perfusion MRI are commonly used techniques for posttreatment glioma surveillance. Using integrated PET-MRI, we assessed the rate of discordance between simultaneously acquired FDG PET images and dynamic contrast-enhanced (DCE) perfusion MR images and determined whether tumor genetics predicts discordance., Materials and Methods: Forty-one consecutive patients with high-grade gliomas (20 with grade IV gliomas and 21 with grade III gliomas) underwent a standardized tumor protocol performed using an integrated 3-T PET-MRI scanner. Quantitative measures of standardized uptake value, plasma volume, and permeability were obtained from segmented whole-tumor volumes of interest and targeted ROIs. ROC curve analysis and the Youden index were used to identify optimal cutoffs for FDG PET and DCE-MRI. Two-by-two contingency tables and percent agreement were used to assess accuracy and concordance. Twenty-six patients (63%) from the cohort underwent next-generation sequencing for tumor genetics., Results: The best-performing FDG PET and DCE-MRI cutoffs achieved sensitivities of 94% and 91%, respectively; specificities of 56% and 89%, respectively; and accuracies of 80% and 83%, respectively. FDG PET and DCE-MRI findings were discordant for 11 patients (27%), with DCE-MRI findings correct for six of these patients (55%). Tumor grade, tumor volume, bevacizumab exposure, and time since radiation predicted discordance between FDG PET and DCE-MRI findings, with an ROC AUC value of 0.78. Isocitrate dehydrogenase gene and receptor tyrosine kinase gene pathway mutations increased the ROC AUC value to 0.83., Conclusion: FDG PET and DCE-MRI show comparable accuracy and sensitivity in identifying tumor progression. These modalities were shown to have discordant findings for more than a quarter of the patients assessed. Tumor genetics may contribute to perfusion-metabolism discordance, warranting further investigation.

Purpose: Texture analysis performed on MR images can detect quantitative features that are imperceptible to human visual assessment. The purpose of this study was to evaluate the feasibility of texture analysis on preoperative conventional MRI to discriminate between histological subtypes in low-grade gliomas (LGGs), and to determine the utility of texture analysis compared to histogram analysis alone., Methods: A total of 41 patients with LGG, 21 astrocytoma and 20 1p/19q codeleted oligodendroglioma were included in this study. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analysis was performed on conventional MRI sequences to obtain the most discriminant factor (MDF) values for both the training and testing data. Receiver operating characteristic (ROC) curve analyses were then performed using the MDF values and 9 histogram parameters in the training data to obtain cut-off values for determining the correct rate of discriminating between astrocytoma and oligodendroglioma in the testing data., Results: The ROC analyses using MDF values resulted in an area under the curve (AUC) of 0.91 (sensitivity 86%, specificity 87%) for T2w FLAIR, 0.94 (87%, 89%) for ADC, 0.98 (93%, 95%) for T1w, and 0.88 (78%, 86%) for T1w + Gd sequences. Using the best cut-off values, MDF correctly discriminated between the two groups in 94%, 82%, 100%, and 88% of cases in the testing data, respectively. The MDF outperformed all 9 of the histogram parameters., Conclusion: Texture analysis performed on conventional preoperative MRI images can accurately predict histological subtype of LGGs, which would have an impact on clinical management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The prognosis of patients with glioblastoma (GBM) remains dismal, with a median survival of approximately 15 months. Current preclinical GBM models are limited by the lack of a "normal" human microenvironment and the inability of many tumor cell lines to accurately reproduce GBM biology. To address these limitations, we have established a model system whereby we can retro-engineer patient-specific GBMs using patient-derived glioma stem cells (GSCs) and human embryonic stem cell (hESC)-derived cerebral organoids. Our cerebral organoid glioma (GLICO) model shows that GSCs home toward the human cerebral organoid and deeply invade and proliferate within the host tissue, forming tumors that closely phenocopy patient GBMs. Furthermore, cerebral organoid tumors form rapidly and are supported by an interconnected network of tumor microtubes that aids in the invasion of normal host tissue. Our GLICO model provides a system for modeling primary human GBM ex vivo and for high-throughput drug screening., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Molecular data has become an essential part of the updated World Health Organization (WHO) grading of central nervous system tumors. However, stereotactic needle biopsies provide only small volume specimens and limit the extent of histologic and molecular testing that can be performed. We assessed the use of a tubular retractor-based minimally invasive biopsy technique to provide improved tissue yield and diagnostic data compared to needle biopsy., Methods: Eighteen patients underwent an open transtubular biopsy compared to 146 stereotactic biopsies during the years of 2010-2018., Results: Tubular biopsies resulted in a higher volume of tissue provided to the pathologist than needle biopsies (1.26 cm 3 vs. 0.3 cm 3 ; p < 0.0001). There was a higher rate of non-diagnostic sample with stereotactic compared to transtubular biopsy (13% vs. 0%; p = 0.13). Six patients who underwent stereotactic biopsy required reoperation for diagnosis, while no transtubular biopsy patient required reoperation in order to obtain a diagnostic specimen. Postoperative hematoma was the most common post-operative complication in both groups., Conclusions: Stereotactic transtubular biopsies are a viable alternative to stereotactic needle biopsies with excellent rates of diagnostic success and acceptable morbidity relative to the needle biopsy technique. As molecular data begins to increasingly drive treatment decisions, additional biopsy techniques that afford large tissue volumes may be necessary to adapt to the new needs of pathologists and treating oncologists.

The Rembrandt brain cancer dataset includes 671 patients collected from 14 contributing institutions from 2004-2006. It is accessible for conducting clinical translational research using the open access Georgetown Database of Cancer (G-DOC) platform. In addition, the raw and processed genomics and transcriptomics data have also been made available via the public NCBI GEO repository as a super series GSE108476. Such combined datasets would provide researchers with a unique opportunity to conduct integrative analysis of gene expression and copy number changes in patients alongside clinical outcomes (overall survival) using this large brain cancer study.

Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets., (© 2017 UICC.)

Glioblastoma, the most common primary malignant brain tumor, harbors a small population of tumor initiating cells (glioblastoma stem cells) that have many properties similar to neural stem cells. To investigate common regulatory networks in both neural and glioblastoma stem cells, we subjected both cell types to in-vitro differentiation conditions and measured global gene-expression changes using gene expression microarrays. Analysis of enriched transcription factor DNA-binding sites in the promoters of differentially expressed genes was used to reconstruct regulatory networks involved in differentiation. Computational predictions, which were biochemically validated, show an extensive overlap of regulatory circuitry between cell types including a network centered on the transcription factor KLF4. We further demonstrate that EGR1, a transcription factor previously shown to be downstream of the MAPK pathway, regulates KLF4 expression and that KLF4 in turn transcriptionally activates NOTCH as well as SOX2. These results demonstrate how known genomic alterations in glioma that induce constitutive activation of MAPK are transcriptionally linked to master regulators essential for neural stem cell identify.

We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7-9/24 (29.2-37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy.

Aim: A Phase II trial of bevacizumab plus tandutinib., Methods: We enrolled 41 recurrent, bevacizumab-naive glioblastoma patients for a trial of bevacizumab plus tandutinib. Median age was 55 and 71% were male. Treatment consisted of tandutinib 500 mg two-times a day (b.i.d.) and bevacizumab 10 mg/kg every 2 weeks starting day 15. Of 37 (90%) evaluable, nine (24%) had partial response., Results & Conclusion: Median overall and progression-free survival was 11 and 4.1 months; progression-free survival at 6 months was 23%. All patients suffered treatment-related toxicities; common grade ≥3 toxicities were hypertension (17.1%), muscle weakness (17.1%), lymphopenia (14.6%) and hypophosphatemia (9.8%). Four of six with grade ≥3 tandutinib-related myasthenic-like muscle weakness had electromyography-proven neuromuscular junction pathology. Tandutinib with bevacizumab was as effective but more toxic than bevacizumab monotherapy.

NF-kB inhibition by bortezomib enhances tamoxifen-induced apoptosis in preclinical glioma models. We conducted a single institution, phase II trial to evaluate efficacy and safety of high dose tamoxifen with bortezomib in adults with recurrent malignant gliomas. The primary endpoint was radiographic response. Concurrent enzyme inducing anticonvulsants and grade ≥2 peripheral neuropathy were exclusion criteria. Patients received tamoxifen (120 mg PO twice daily) and bortezomib (1.3 mg/m2 IV on days 3, 6, 10, 13, 24, 27, 31, and 34) per 6-week cycles. We enrolled 42 patients with anaplastic gliomas (AGs, n = 12) and glioblastomas (GBMs, n = 30), 32 males and 10 females. Median age was 38 years (range 22-65) and 48 years (range 19-68) for AGs and GBMs, respectively. median karnofsky performance status was 90% (range 70-100) for AGs and 80% (range 60-100) for GBMs. Median prior therapies was 3, ranging 1-7. Grade ≥3 toxicities included lymphopenia (4/42), hypophosphatemia (3/42), thromobocytopenia (2/42), and 1/42 with hyponatremia, headache, dyspnea, or DVT. One patient withdrew consent, two were removed for toxicity, and all others discontinued for progression. Among 40 patients evaluable for response, only one achieved stable disease for 3 months; all others progressed rapidly. For AGs and GBMs respectively, median progression-free survival was 5.9 and 5.7 weeks and median overall survival was 25.6 and 14.7 weeks. The study was closed due to poor accrual and therapeutic futility. Combination tamoxifen and bortezomib has no activity in recurrent malignant gliomas. Poor penetration across blood brain barrier of bortezomib likely limited efficacy.

Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM., Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment)., Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels., Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study., (Published by Elsevier Inc.)

Glioblastoma is one of the deadliest human cancers. There have been few significant therapeutic advances in the field over the past two decades, with median survival of only about 15 months despite aggressive neurosurgery, radiotherapy, and chemotherapy. Nevertheless, the past 5 years has seen an explosion in our understanding of the genetic and molecular underpinnings of these tumors, leading to renewed optimism about potential new therapeutic approaches. Several of the most promising new approaches include oncogenic signal transduction inhibition, angiogenesis inhibition, targeting canonical stem cell pathways in glioblastoma stem cells, and immunotherapy. As promising as many of these approaches appear, they have not had an impact yet on the natural history of the disease or on patient long-term outcomes. Nevertheless, it is hoped that with time such approaches will lead to more effective treatments, but issues such as the unique biology and anatomy of the central nervous system, impaired drug delivery, poor preclinical models with resultant nonpredictive preclinical screening, and poor clinical trial design potentially impede the rapid development of such new therapies. In this article, we review the excitement and challenges that face the development of effective new treatments that exploit this new biology., (©2015 American Association for Cancer Research.)

During the last decade, extensive multiplatform genome-wide analysis has yielded a wealth of knowledge regarding the genetic and molecular makeup of glioblastoma multiforme (GBM). These profiling studies support the emerging view that GBM comprises a group of highly heterogeneous tumor types, each with its own distinct molecular and genetic signatures. This heterogeneity complicates the process of defining reliable intertumor/intratumor biological states, which will ultimately be needed for classifying tumors and for designing effective customized therapies that target resultant disease pathways. The increased understanding of the molecular pathogenesis of GBM has brought the hope and expectation that such knowledge will lead to better and more rational therapies directed toward specific molecular targets. To date, however, these expectations have largely been unrealized. This review discusses some of the principal genetic and epigenetic aberrations found in GBM that appear promising for targeted therapies now and in the near future, and it offers suggestions for future directions concerning the rather disappointing results of clinical trials to date., (© 2014 American Cancer Society.)

Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

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., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established., Experimental Design: The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging., Results: At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005., Conclusions: Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.

Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs.

Bevacizumab ((BEV) has become a mainstay of treating recurrent glioblastoma, but eventual tumor resistance is expected. Targeting multiple growth-associated signaling pathways may result in more effective treatment than targeting VEGF alone. Patients with recurrent glioblastoma were stratified by prior BEV exposure and treated with sunitinib 37.5 mg daily in this phase II study. Response evaluations were performed at baseline and at the end of every 4 week cycle. Six-month progression-free survival (PFS6) was the primary endpoint for both arms of the study. Secondary endpoints included health related quality of life measures and FDG-PET correlatives with patient outcomes. Sixty-three patients were accrued to this study; thirty-two were BEV-naïve, 31 were BEV-resistant. PFS6 was 10.4 % [95 % CI 3.2-33.8] in the BEV-naïve cohort and 0 % in the BEV-resistant cohort. Median overall survival was 9.4 months [95 % CI 6.15-21.90] in the BEV-naïve cohort and 4.37 months [95 % CI 3.02-6.21] in the BEV-resistant cohort. 3/29 patients (10 %) of the BEV-naïve, and 0/27 BEV-resistant patients achieved radiographic response. Thrombocytopenia, leukopenia, and neutropenia were the most common drug-associated adverse events and occurred with higher frequency than expected. Sunitinib treatment in BEV-naïve patients did not appear to affect outcomes with subsequent BEV therapy. Continuous daily sunitinib did not prolong progression-free survival in BEV-naïve nor BEV-resistant patients with recurrent glioblastoma.

The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.

Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.

Glioblastoma multiforme is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the retinoblastoma, phosphoinositide-3 kinase (PI3K), and p53 pathways are molecular hallmarks of this disease. Recent work has shown that p53(-/-)Pten(-/-) mice form gliomas in a c-Myc-dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten(-/-)Ink4a/Arf(-/-) mouse neural stem cells (mNSC) and such cells were highly proliferative, self-renewing, relatively refractory to differentiation, and induced both low- and high-grade glioma formation in vivo. In contrast to p53(-/-) Pten(-/-) mNSCs, however, Pten(-/-)Ink4a/Arf(-/-) mNSCs do not express appreciable levels of c-Myc in vitro, although glioma stem cells derived from thesecells did. Sequencing of Pten(-/-)Ink4a/Arf(-/-) mNSC-derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten(-/-)Ink4a/Arf(-/-) mNSC or knockdown of Fbxw7 resulted in reexpression of c-Myc with enhanced Pten(-/-)Ink4a/Arf(-/-) mNSC tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis., (©2012 AACR.)

No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies for glioblastoma, we sought to target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative of glioma tumors than established glioma cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result of a novel tumor-specific gene rearrangement that produces a unique protein expressed in approximately 30% of gliomas, and is an ideal target for immunotherapy. Using PCR primers spanning the EGFRvIII-specific deletion, we found that this tumor-specific gene is expressed in three of three GCS lines. Based on the sequence information of seven EGFRvIII-specific monoclonal antibodies (mAbs), we assembled chimeric antigen receptors (CARs) and evaluated the ability of CAR-engineered T cells to recognize EGFRvIII. Three of these anti-EGFRvIII CAR-engineered T cells produced the effector cytokine, interferon-γ, and lysed antigen-expressing target cells. We concentrated development on a CAR produced from human mAb 139, which specifically recognized GSC lines and glioma cell lines expressing mutant EGFRvIII, but not wild-type EGFR and did not recognize any normal human cell tested. Using the 139-based CAR, T cells from glioblastoma patients could be genetically engineered to recognize EGFRvIII-expressing tumors and could be expanded ex vivo to large numbers, and maintained their antitumor activity. Based on these observations, a γ-retroviral vector expressing this EGFRvIII CAR was produced for clinical application.

As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function.

Unlabelled: Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types., Significance: 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., (© 2012 AACR)

Glioneuronal tumor with neuropil-like islands (GTNI) is considered a rare variant of astrocytoma, characterized by discrete aggregates of cells expressing neuronal markers that punctuate a GFAP-positive glial background. Of the 24 published GTNI cases, only two occurred in adult spinal cords; none occurred concurrent with another CNS tumor; and none of those tested exhibited the 1p/19q deletion typical of oligodendroglioma. A 48-year-old man without significant past medical history was diagnosed with a WHO grade II oligodendroglioma by stereotactic biopsy of a lesion discovered after the patient suffered a generalized tonic-clonic seizure. By FISH analysis, this tumor exhibited the 1p/19q deletion present in up to 80% of oligodendrogliomas. The patient received 14 monthly cycles of temozolomide, and his cerebral tumor had a minor response. When the patient subsequently reported progressive paresthesias of his lower extremities, an MRI revealed an enhancing, cystic tumor of the thoracic spinal cord that was diagnosed as GTNI by histological analysis. By FISH analysis, this lesion exhibited the same 1p/19q deletion present in the concurrent cerebral oligodendroglioma. This case of a spinal cord GTNI with 1p/19q deletions constitutes the third report of a spinal cord GTNI in an adult patient; the first report of a GTNI in an individual with a separate CNS neoplasm; and the first report of a GTNI with 1p/19q deletions. This case establishes a potential genetic kinship between GTNI and oligodendroglioma that warrants further investigation.

Glioblastoma Multiforme (GBM) is a tumor with high mortality and no known cure. The dramatic molecular and clinical heterogeneity seen in this tumor has led to attempts to define genetically similar subgroups of GBM with the hope of developing tumor specific therapies targeted to the unique biology within each of these subgroups. Recently, a subset of relatively favorable prognosis GBMs has been identified. These glioma CpG island methylator phenotype, or G-CIMP tumors, have distinct genomic copy number aberrations, DNA methylation patterns, and (mRNA) expression profiles compared to other GBMs. While the standard method for identifying G-CIMP tumors is based on genome-wide DNA methylation data, such data is often not available compared to the more widely available gene expression data. In this study, we have developed and evaluated a method to predict the G-CIMP status of GBM samples based solely on gene expression data.

Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ., Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts., Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year., Conclusion: 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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received FDA approval for recurrent glioblastoma. Additionally, several VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have entered trials for recurrent glioma. Phase II studies of bevacizumab for recurrent GBM have reported incidents of ischemic stroke (IS) and intracranial hemorrhage (ICH); however, their clinical features and outcomes were not described in detail. We conducted a retrospective study of recurrent malignant glioma patients with radiographically-confirmed IS or ICH while on antiangiogenic therapy. The study population included patients treated between 2005 and 2010 at the National Cancer Institute on four different phase I and II trials of antiangiogenic agents for recurrent malignant glioma, as well as patients receiving bevacizumab off clinical trial during this same period. Eight patients developed IS (50% lacunar) and 14 experienced ICH (79% intratumoral) while on antiangiogenic therapy for malignant glioma recurrence. The median age was 53 years, 17 patients (77%) were men, and 59% had glioblastoma. The frequencies of IS and ICH were 1.9% and 1.9% in bevacizumab trials. None of the patients on VEGFR TKI trials developed IS, while 3.8% experienced ICH. Patients with IS were treated with antiangiogenic agents longer than those with ICH (median, 16.2 vs. 2.6 months, P = 0.001). Median survival was 7.8 months after IS and 2.6 months after ICH. The most common IS subtype was lacunar, while most ICHs were asymptomatic and intratumoral. Overall, IS seems to be a complication of prolonged antiangiogenic therapy, while intratumoral bleeds often occur in the setting of tumor progression.

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.

The purpose of this study was to evaluate the activity of single-agent bevacizumab in patients with recurrent anaplastic glioma and assess correlative advanced imaging parameters. Patients with recurrent anaplastic glioma were treated with bevacizumab 10 mg/kg every 2 weeks. Complete patient evaluations were repeated every 4 weeks. Correlative dynamic contrast-enhanced MR and (18)fluorodeoxyglucose PET imaging studies were obtained to evaluate physiologic changes in tumor and tumor vasculature at time points including baseline, 96 h after the first dose, and after the first 4 weeks of therapy. Median overall survival was 12 months (95% confidence interval [CI]: 6.08-22.8). Median progression-free survival was 2.93 months (95% CI: 2.01-4.93), and 6-month progression-free survival was 20.9% (95% CI: 10.3%-42.5%). Thirteen (43%) patients achieved a partial response. The most common grade ≥ 3 treatment-related toxicities were hypertension, hypophosphatemia, and thromboembolism. Single-agent bevacizumab produces significant radiographic response in patients with recurrent anaplastic glioma but did not meet the 6-month progression-free survival endpoint. Early change in enhancing tumor volume at 4 days after start of therapy was the most significant prognostic factor for overall and progression-free survival.

Background: Tumor cell invasion is the principal cause of treatment failure and death among patients with malignant gliomas. Connective tissue growth factor (CTGF) has been previously implicated in cancer metastasis and invasion in various tumors. We explored the mechanism of CTGF-mediated glioma cell infiltration and examined potential therapeutic targets., Methods: Highly infiltrative patient-derived glioma tumor-initiating or tumor stem cells (TIC/TSCs) were harvested and used to explore a CTGF-induced signal transduction pathway via luciferase reporter assays, chromatin immunoprecipitation (ChIP), real-time polymerase chain reaction, and immunoblotting. Treatment of TIC/TSCs with small-molecule inhibitors targeting integrin β1 (ITGB1) and the tyrosine kinase receptor type A (TrkA), and short hairpin RNAs targeting CTGF directly were used to reduce the levels of key protein components of CTGF-induced cancer infiltration. TIC/TSC infiltration was examined in real-time cell migration and invasion assays in vitro and by immunohistochemistry and in situ hybridization in TIC/TSC orthotopic xenograft mouse models (n = 30; six mice per group). All statistical tests were two-sided., Results: Treatment of TIC/TSCs with CTGF resulted in CTGF binding to ITGB1-TrkA receptor complexes and nuclear factor kappa B (NF-κB) transcriptional activation as measured by luciferase reporter assays (mean relative luciferase activity, untreated vs CTGF(200 ng/mL): 0.53 vs 1.87, difference = 1.34, 95% confidence interval [CI] = 0.69 to 2, P < .001). NF-κB activation resulted in binding of ZEB-1 to the E-cadherin promoter as demonstrated by ChIP analysis with subsequent E-cadherin suppression (fold increase in ZEB-1 binding to the E-cadherin promoter region: untreated + ZEB-1 antibody vs CTGF(200 ng/mL) + ZEB-1 antibody: 1.5 vs 6.4, difference = 4.9, 95% CI = 4.8 to 5.0, P < .001). Immunohistochemistry and in situ hybridization revealed that TrkA is selectively expressed in the most infiltrative glioma cells in situ and that the surrounding reactive astrocytes secrete CTGF., Conclusion: A CTGF-rich microenvironment facilitates CTGF-ITGB1-TrkA complex activation in TIC/TSCs, thereby increasing the invasiveness of malignant gliomas.

Primary brain tumors are a leading cause of cancer-related mortality among young adults and children. The most common primary malignant brain tumor, glioma, carries a median survival of only 14 months. Two major multi-institutional programs, the Glioma Molecular Diagnostic Initiative and The Cancer Genome Atlas, have pursued a comprehensive genomic characterization of a large number of clinical glioma samples using a variety of technologies to measure gene expression, chromosomal copy number alterations, somatic and germline mutations, DNA methylation, microRNA, and proteomic changes. Classification of gliomas on the basis of gene expression has revealed six major subtypes and provided insights into the underlying biology of each subtype. Integration of genome-wide data from different technologies has been used to identify many potential protein targets in this disease, while increasing the reliability and biological interpretability of results. Mapping genomic changes onto both known and inferred cellular networks represents the next level of analysis, and has yielded proteins with key roles in tumorigenesis. Ultimately, the information gained from these approaches will be used to create customized therapeutic regimens for each patient based on the unique genomic signature of the individual tumor. In this Review, we describe efforts to characterize gliomas using genomic data, and consider how insights gained from these analyses promise to increase understanding of the biological underpinnings of the disease and lead the way to new therapeutic strategies.

Romidepsin, a potent histone deacetylase inhibitor, has shown activity in preclinical glioma models. The primary objectives of this trial were to determine the pharmacokinetics of romidepsin in patients with recurrent glioma on enzyme-inducing antiepileptic drugs (EIAEDs) and to evaluate the antitumor efficacy of romidepsin in patients with recurrent glioblastoma who were not receiving EIAEDs. Two dose cohorts were studied in the phase I component of the trial (13.3 and 17.7 mg/m(2)/d). Patients in the phase II component were treated with intravenous romidepsin at a dosage of 13.3 mg/m(2)/day on days 1, 8, and 15 of each 28-day cycle. Eight patients were treated on the phase I component. A similar romidepsin pharmacokinetic profile was demonstrated between patients receiving EIAEDs to those not receving EIAEDs. Thirty-five patients with glioblastoma were accrued to the phase II component. There was no objective radiographic response. The median progression-free survival (PFS) was 8 weeks and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). To date, 34 patients (97%) have died, with a median survival duration of 34 weeks. Despite in vitro studies showing that romidepsin is primarily metabolized by CYP3A4, no decrease in exposure to romidepsin was seen in patients receiving potent CYP3A4 inducers. Romidepsin, at its standard dose and schedule, was ineffective for patients with recurrent glioblastomas. ClinicalTrials.gov identifier: NCT00085540.

Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1 06 (OR=1.67, 95% CI=1.17-2.39) and DRB1 13 (OR=1.69, 95% CI=1.08-2.64) alleles were associated with an increased risk of glioma, while the DQB1 05 allele showed an inverse association (OR=0.63, 95% CI=0.43-0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1 06, DQB1 05, and DRB1 13 alleles in glioma susceptibility., (Copyright © 2010. Published by Elsevier B.V.)