UCLA

Glioblastoma (GBM) remains the most common and lethal primary brain tumor in adults despite concerted efforts to establish more effective treatments. The oncogenic-associated alterations that make GBM cells metabolically distinct from surrounding tissue also represent prime targets for the development of novel therapies. Due to the interconnectivity of signaling networks and the overall heterogeneity of the disease, identifying key metabolic pathways that drive neoplastic pathogenesis is essential to establishing more effective therapeutic strategies. In this dissertation, we performed expression analysis and unbiased metabolomics to better characterize metabolic differences between a cohort of patient-derived isocitrate dehydrogenase 1 (IDH1) mutant and wildtype gliomasphere cultures. This analysis revealed clear, cell type-specific differences in glucose metabolism, nucleotide synthesis utilization, and DNA repair capacity following radiation that could be exploited for therapy. Furthermore, we investigated the ability of GBM cells to oxidize fatty acids (FAO) and ketone bodies to support tumor growth, while also interrogating the effectiveness of the ketogenic diet (KD) as an adjuvant therapy for GBM. We discovered extensive FAO utilization throughout the GBM metabolome, identified CPT1A as a potential therapeutic target, and determined that the KD can have adverse effects on tumor growth.