Genotype and Metabolic Phenotype in Glioblastoma

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DESCRIPTION (provided by applicant): Glioblastoma, the most common primary brain tumor in adults, is considered to be among the deadliest of human cancers. With a median survival time of 14.6 months and approximately 25% of patients alive at 2 years after the most aggressive treatment regimens, there is clearly a desperate need to improve the understanding of basic biological processes in glioblastoma. The molecular aberrations underlying this disease have been extensively characterized and an important framework of critical cancer pathways involved in glioblastoma growth and survival has emerged, centered prominently on activation of the RAS/MAPK pathway and dysregulation of the PI3Kinase pathway. However, targeted inhibition of these and other molecular pathways in glioblastoma patients has been largely ineffective and, as a result, there is increasing interest in understanding mechanisms of altered metabolism since it represents a 'functional readout' of the constellation of genetic mutations that interact to influence cell growth and survival. The characteristic and well established metabolic features of glioblastoma - intense glucose uptake on FDG-PET, abundant lactate production, and a defect in NADP+ - dependent isocitrate dehydrogenase - may be interconnected events due to a specific genetic mutation. Alternatively, these features may be a common endpoint reflecting redundancy in the cancer cell's genetic program. To address basic questions related to the genotype-metabolic phenotype connection in glioblastoma we have engaged a multidisciplinary team of physicians and scientists in a clinical and translational study designed to identify the critical metabolic pathways that drive unregulated tumor cell proliferation in the brain microenvironment in vivo. In Aim 1 we will define the metabolic phenotype of glioblastoma in a novel human orthotopic mouse model by 13C NMR spectral analysis of genetically characterized tumors following infusion of [U-13C]glucose or [1,2-13C]glucose to assess, respectively, the pathways intersecting in the citric acid cycle and relative flux through the pentose phosphate pathway. Specifically, we will determine whether the FDG signature of glioblastoma - increased glucose uptake - is feeding one or some combination of three pathways: excess anaerobic glycolysis to lactate, excess aerobic glycolysis to pyruvate followed by oxidation in the citric acid cycle, or excess flux through the pentose phosphate pathway to support proliferation or to compensate for loss of NADPH production due to mutation of IDH-1. In Aim 2 we will define the metabolic phenotype in glioblastoma patients undergoing surgical resection for presumed high grade glioma. In each patient, 13C NMR spectral analysis of tumor extracts will be obtained after intra-operative infusion of [U-13C]glucose or [1,2-13C]glucose. Results will be correlated with preoperative imaging by FDG-PET, ultra high resolution MR imaging on a 7T magnet, diffusion tensor imaging and 1H-spectroscopy to generate a comprehensive non-invasive view of the tumor with the goal of identifying infiltrative, metabolically active tumor cells within the brain. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most common primary brain tumor and is considered to be among the deadliest of human cancers. The metabolism of the cells is much higher than normal cells and, like many cancers, represents a possible target for new drugs in cancer therapy. Our proposed research will dissect the metabolic pathways that are abnormal in glioblastoma in a concerted effort to develop new therapies quickly.