Metabolic Resistance to Hypoxia in Glioblastoma Multiforme

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Abstract The malignant brain tumor Glioblastoma (GBM) is a tragic illness for patients and families due to poor patient prognosis, with only 9.8% of patients surviving past 5 years. Only modest gains in survival have been made despite decades of research, therefore, a better understanding of the basic biology of this disease is needed to improve patient outcomes. Hypoxia is characteristic of GBM and many other tumors, and is increased by the anti-angiogenic agent bevacizumab, which is commonly used for recurrent GBM tumors. Metabolic changes contribute to adaptation to tumor hypoxia, and can be potentially targeted to reduce treatment resistance. Our preliminary data shows elevated levels of triglycerides and decreased levels of very long chain fatty acids in highly hypoxic tumors. This suggests the use of peroxisomal fatty acid oxidation which primarily catabolizes very long chain fatty acids, as a fuel source in highly hypoxic tumors. In addition, previous studies show that hypoxia induces secretion of triglyceride-loaded extracellular vesicles in prostate cancer cells. Triglyceride-loaded extracellular vesicles may be a potential mechanism for delivering fuel sources to GBM cells during hypoxia. We hypothesize that GBM cells rely on peroxisomal fatty acid oxidation and triglyceride-loaded extracellular vesicle secretion to fuel tumor growth during hypoxia. We will investigate this hypothesis through our specific aims: 1) determine the effect of peroxisomal fatty acid oxidation in adaptation to hypoxia induced by anti-angiogenic treatment in GBM tumors, and 2) define the role of extracellular vesicle formation and lipid secretion in adaptation to hypoxia induced by anti-angiogenic treatment in GBM tumors. To address both of these specific aims, we will 1) determine the lipid metabolism effects of hypoxia on cells and extracellular vesicles in vitro using metabolomics and mRNA analysis, and 2) test the efficacy of combining inhibitors targeting peroxisomal fatty acid oxidation or triglyceride synthesis with anti-angiogenic treatment both in vitro and in vivo. When using these inhibitors, we expect to see 1) inhibition of cell growth in vitro in cells exposed to hypoxia, and 2) inhibition of tumor growth and extension of survival for tumors treated with anti-angiogenic treatment and our inhibitory agents, compared to either treatment alone. These studies are significant in that they will elucidate mechanisms for tumor growth and resistance to treatment. The identified mechanisms can be targeted and incorporated into innovative treatment regimens for GBM patients, potentially leading to substantial increases in survival and patient well-being.