METB-03TARGETING CANCER CELL METABOLISM IN GLIOBLASTOMA

Abstract

RATIONALE: Hypoxia contributes to high tumor grade in human glioblastoma and is associated with resistance to radiation and chemotherapy. Hypoxia is generally encountered in perinecrotic regions throughout the heterogeneous tumor microenvironment and may be due to rapid tumor grow, insufficient neovascularization or as a result of antiangiogenic and chemoradiation therapies which cause acute vascular thrombosis. Cancer stem-like cells residing within these hypoxic zones compensate for the low concentration of oxygen through alterations in metabolism that favor aerobic glycolysis and de novo fatty acid synthesis. These metabolic derangements are known to enhance proliferation and survival, although the contributing molecular mechanisms are not fully understood. Here we evaluate a panel of FDA approved azole drugs for alternative use as glycolytic hexoinase 2 inhibitors with and without the fatty acid synthase (FASN) inhibitor, TBV-3166. TVB-3166 is currently in phase II clinical trials and is the first FASNi approved for human testing. METHODS: IC50 values of single or combined agents were determined by MTT under conditions of normoxia and hypoxia using sister plates of the commercial GBM cell lines, U87 and T98. Because the combination of Itraconazole and TVB-3166 displayed a synergistic enhancement in cell death at low nanomolar concentrations in GBM cells, we next assessed the efficacy of these drugs on clonogenic potential. Here, 100 cells were seeded onto 10 cm2 plates and grown under normoxic or hypoxic conditions for 10 days after exposure to single or combined agents. After 10 days post-treatment the plates treated with the combination of metabolic inhibitors exhibited best response. CONCLUSION: Given the significant clonogenic response to the combination of metabolic inhibitors, additional studies that further evaluate the chemotherapeutic effects of these metabolic inhibitors are warranted. By targeting hypoxia-induced metabolic pathways, we may enhance cancer stem-like cell death and eventually improve patient outcome.