BACKGROUND Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. METHODS We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy. RESULTS A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. CONCLUSIONS In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.)

Metabolic reprogramming is a hallmark of cancer. Oncogenic growth signaling regulates glucose, glutamine and lipid metabolism to meet the bioenergetics and biosynthetic demands of rapidly proliferating tumor cells. Emerging evidence indicates that sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that controls lipid metabolism, is a critical link between oncogenic signaling and tumor metabolism. We recently demonstrated that SREBP-1 is required for the survival of mutant EGFR-containing glioblastoma, and that this pro-survival metabolic pathway is mediated, in part, by SREBP-1-dependent upregulation of the fatty acid synthesis and low density lipoprotein (LDL) receptor (LDLR). These results have identified EGFR/PI3K/Akt/SREBP-1 signaling pathway that promotes growth and survival in glioblastoma, and potentially other cancer types. Here, we summarize recent insights in the understanding of cancer lipid metabolism, and discuss the evidence linking SREBP-1 with PI3K/Akt signaling-controlled glycolysis and with Myc-regulated glutaminolysis to lipid metabolism. We also discuss the development of potential drugs targeting the SREBP-1-driven lipid metabolism as anti-cancer agents.

SUMMARY Malignant gliomas are one of the most treatment-refractory cancers. Development of resistance to chemo- and radio-therapies contributes to these tumors’ aggressive phenotypes. Elevated lipid levels in gliomas have been reported for the last 50 years. However, the molecular mechanisms of how tumor tissues obtain lipids and utilize them are not well understood. Recently, the oncogenic signaling EGFR/PI3K/Akt pathway has been shown to enhance lipid synthesis and uptake by upregulating SREBP-1, a master transcriptional factor, to control lipid metabolism. This article discusses the analytical chemistry results of lipid components in glioma tissues from different research groups. The molecular mechanisms that link oncogenes with lipid programming, and identification of the key molecular targets and development of effective drugs to inhibit lipid metabolism in malignant gliomas will be discussed.

Glioblastoma (GBM) is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric di-methylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell cycle arrest, apoptosis and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Lastly, PRMT5 attenuation enhanced GBM cell survival in a mouse xenograft model of aggressive GBM. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in GBM, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease.

ClinicalTrials.gov Identifier: NCT00114140.

PURPOSE NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Purpose Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from platinum-based chemotherapy. We hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a novel predictive biomarker of increased sensitivity to adjuvant platinum-based therapies in NSCLC. Experimental Design The prognostic value was tested using a gene expression microarray from the Director’s Challenge Lung Study (n=440). The predictive significance of SMARCA4 was determined using a gene expression microarray (n=133) from control and treatment arms of the JBR.10 trial of adjuvant cisplatin/vinorelbine. Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival (OS) and disease-specific survival (DSS) between expression groups and treatment arms. Multivariate Cox regression models were used while adjusting for other clinical covariates. Results In the Director’s Challenge Study, reduced expression of SMARCA4 was associated with poor OS compared to high and intermediate expression (P<0.001 and P=0.009, respectively). In multivariate analysis, compared to low, high SMARCA4 expression predicted a decrease in risk of death (HR=0.6, 95% CI: 0.4–0.8, P=0.002). In the JBR.10 trial, improved five-year DSS was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine (HR=0.1, 95% CI: 0.0–0.5, P=0.002 [low]; HR 1.0, 95% CI: 0.5–2.3, P=0.92 [high]). An interaction test was highly significant (P=0.01). Conclusions Low expression of SMARCA4/BRG1 is significantly associated with worse prognosis; however, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC.

Importance The need for a more refined, molecularly-based classification model for glioblastoma (GBM) in the temozolomide era. Objective Refine the existing clinically-based recursive partitioning analysis (RPA) model by incorporating molecular variables. Design, Setting, and Participants NRG Oncology RTOG 0525 specimens (n=452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semi-quantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multi-marker Cox-regression analyses. In order to reclassify the prognostic risk groups, significant protein biomarkers upon single-marker analysis were incorporated into a RPA model consisting of the same clinical variables (age, KPS, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent dataset (n=176). Main Outcomes and Measures Overall survival (OS) Results MGMT (HR=1.81, 95% CI(1.37, 2.39), p<0.001), survivin (HR=1.36, 95% CI(1.04, 1.76), p=0.02), c-Met (HR=1.53, 95% CI(1.06,2.23), p=0.02), pmTOR (HR=0.76, 95% CI(0.60,0.97), p=0.03), and Ki-67 (HR=1.40, 95% CI(1.10, 1.78), p=0.007), were found to be significant upon single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, performance status, extent of resection, and neurological function) were incorporated into a new model. Higher MGMT protein was significantly associated with decreased MGMT promoter methylation and vice-versa. Further, MGMT protein expression had greater prognostic value for OS compared to MGMT promoter methylation. The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared to the existing clinically-based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM-RPA was subsequently confirmed in an independent dataset (N=176). Conclusions and Relevance The new NRG-GBM-RPA model significantly enhances outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for GBM patients treated with radiation and temozolomide and was biologically validated in an independent dataset. The revised RPA has the potential to significantly contribute to improving the accurate assessment of prognostic groups in GBM patients treated with radiation and temozolomide and also influence clinical decision making.