Glioblastoma Multiforme Therapeutics Research Articles

Age-Specific Signatures of Glioblastoma at the Genomic, Genetic, and Epigenetic Levels

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.

Abstract 3688: Akt pathway genes classify GBM into 6 prognostic subgroups with different clinical and molecular features

Abstract The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known if akt pathway variations exist in GBM tumors. To investigate we developed a list of Akt pathway genes and investigated expression subgroups in a set of human GBM. Akt classification divides GBM into 6 subgroups with differing survivals and clinical/molecular features. Median survival of patients in the longest surviving subgroup (subgroup 5) was 3.9 yr vs 0.75 yr for patients in the shortest surviving subgroup (p < 0.01 Bonferroni corrected log rank). Patients in the long surviving subgroup were younger than the rest (median age = 38 vs 49 respectively; p = 0.05 corrected for multiple comparisons), but survival differences were independent of age (p = 0.027; subgroup 5 vs the rest). Tumors in short surviving subgroups were characterized by chr7 gain, chr10 loss and high ser473 phosphorylated-akt (p-akt) staining. The long surviving subgroup tumors were enriched for chr19q loss, low p-akt staining, elevated Notch staining and had no DNA copy number alterations in chr7 or chr10. Previously described subgroups (Phillips et.al.) were enriched in akt subgroups (all with p<0.001). These results suggest that tumors with a pathological diagnosis of GBM are a collection of molecular subgroups with fundamental differences in biology and clinical behavior. We hypothesize that Akt subgroups will enhance drug discovery and help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation (BGF and AMJ), Halle Family Foundation (BGF), and NIH 1 K01 NS064952-01A1 (AMJ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3688. doi:1538-7445.AM2012-3688

Abstract 4138: Five prognostic subgroups differ in expression of Akt pathway genes: Biomarkers for therapy selection

Abstract Biomarkers that select patients for therapeutics would benefit clinical trial design and patient care. The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known whether activity of this pathway varies among GBM tumors. To investigate we used Akt pathway genes from published GBM expression datasets. We detected 5 patterns of Akt pathway gene expression and these Akt subgroups correlated with prognosis. We analyzed networks within subgroups using both gene set enrichment analysis and a novel method that scores relevance based on both expression and local network connectivity (Komurov et al., PLoS Comput Biol. 2010 6:8, 1-10). The results suggest therapeutic targets within the individual subgroups. Furthermore, preliminary analysis indicates that human GBM xenograft models and primary human GBM manifest similar Akt subgroups. We are investigating rodent xenograft models of Akt subgroups to evaluate subgroup-specific drug sensitivity, and will present a method and examples of analysis integrating gene expression data from human GBM xenografts and primary human GBM. We hypothesize that Akt subgroups will help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation, Halle Family Foundation, and NIH 1 K01 NS064952-01A1 (AMJ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4138. doi:10.1158/1538-7445.AM2011-4138

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.