Tumor-specific alterations at the p53 gene locus in 30 human vestibular schwannomas (VS) comprising 10 confirmed NF2 cases and 20 sporadic cases were analyzed. We found loss of heterozygosity (LOH) at the first intron of the p53 gene locus in 54% of the informative cases. This is the first report showing LOH at the p53 gene locus in a significant number of human VS and both sporadic and NF2 cases show the LOH event. Increased levels of normal size p53 mRNA and p53 protein were found in all the tumors analyzed. Thus p53 appears to be deregulated in all the tumors suggesting that p53 alterations may be associated with tumor progression in VS. There was a negative significant correlation of patients' age and percentage of Ser 392 phosphorylated p53 protein. The tumor samples obtained from younger patients of 35 yr and below showed higher percentage of Ser 392 phosphorylated p53 protein compared to the tumors of older patients. The increased percentage of Ser 392 phosphorylated p53 protein indicates that it could be involved in the acceleration of tumor growth in the younger patients. Our results suggest that age dependent phosphorylation of p53 protein and deregulation of p53 gene has a role in the development of human vestibular schwannomas.

Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;} Despite considerable progress in understanding the molecular alterations in Glioblastoma (GBM), the diverse metabolic programs driving their aggressive phenotype remains unclear. We performed global metabolomic profiling in patient-derived GBM (n=80) and low-grade glioma (LGG; n=28). Hierarchical clustering of profiles identified clear metabolic programs differentiating LGG from GBM. GBM had an accumulation of metabolites that appeared mutually exclusive compared to LGG, a majority of which was involved in lipid and peptide metabolism. We next examined metabolic heterogeneity within GBM. Hierarchical clustering identified unique metabolic subtypes in GBM. The first subtype, which represented <10% of the tumors analyzed, was defined by an accumulation of lysolipids, a second subtype, by alterations in amino acid, nucleotide, and lipid metabolism. The third subtype, which comprised the majority of tumors, had a unique accumulation of dipeptides in addition to a heterogeneous accumulation of the metabolites of the first two subtypes. To understand the molecular underpinnings of the metabolic heterogeneity in GBM, integrative analysis using gene expression profiles of matched tumors was performed. Preliminary analyses determined that metabolic heterogeneity in GBM is associated with known molecular subtypes, demonstrating mutual exclusivity of the proneural and mesenchymal metabolic profiles, consistent with their molecular signatures. MGMT methylated and IDH mutated tumors were evenly distributed within the metabolic subtypes, indicating that conserved metabolic programs associated with phenotypic changes are required for gliomagenesis. As aberrant fatty acid metabolism, amino acid metabolism, and accumulation of dipeptides represented core metabolic pathways differentiating LGG from GBM and appeared to contribute towards metabolic heterogeneity, we studied these pathways in further detail. Integrated cross-platform analyses uncovered a tightly orchestrated and highly redundant transcriptional program designed to drive the observed metabolic phenotype, also observed in preclinical models. Collectively, integrated metabolomic and genomic analyses helps in both, understanding biologic processes associated with gliomagenesis and identification of novel therapeutic targets. Citation Format: Antony Dayalan, Pravin Kesarwani, Shiva Kant, Prakash Chinnaiyan. Integrative metabolomic and genomic analysis of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3478.

Glioblastoma represents an aggressive, primary brain tumor with limited treatment options. We performed an integrative, cross-platform analysis coupling global metabolomics and gene expression profiling in >100 patient-derived gliomas to begin to understand the diverse metabolic programs driving the aggressive phenotype of this malignancy. Alterations in fatty acid β-oxidation (FAO) emerged as a key metabolic node differentiating glioblastoma from low-grade astrocytoma, as demonstrated by an accumulation of acylcarnitines. Metabolic heterogeneity was observed within glioblastoma that could further define tumors as FAO ‘high’ and ‘low’. Integrative analyses identified these metabolic subtypes to be enriched with mesenchymal (MES) and proneural (PN) glioblastoma subtypes, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models. Analysis of gene expression profiles from these lines uncovered an orchestrated transcriptional program designed to promote fatty acid uptake, activation, and mitochondrial oxidation. Studies designed to determine the biologic consequence of enhanced FAO in glioblastoma only identified a role in glucose-deprived conditions, where it served as a vital, alternate source for ATP synthesis. Based on these findings, we tested the hypothesis that dual targeting of glycolysis and FAO would elicit energetic stress-mediated cell death in glioblastoma. Accordingly, the glycolysis inhibitor 2DG and the FAO inhibitor etomoxir only demonstrated anti-proliferative activity in MES glioblastoma cell lines when used as single agents in vitro, while the combination resulted in robust, necroptosis-mediated cell death. Synergistic anti-tumor activity was observed following combined glycolysis and FAO inhibition when extended in vivo in an orthotopic model. Collectively, our findings suggest FAO provides metabolic plasticity in MES glioblastoma, allowing these cells to adapt to nutrient-deprived microenvironments. Combinatorial strategies designed to inhibit glycolysis and FAO represents an attractive therapeutic approach in glioblastoma. Citation Format: Shiva Kant, Antony Dayalan, Pravin Kesarwani, Prakash Chinnaiyan. Fatty acid oxidation represents a metabolic vulnerability in glioblastoma in nutrient-deprived conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5259.

No abstract