TMET-22. ENHANCED LIPID METABOLISM IN BRAIN TUMORS: AN EXPLOITABLE METABOLIC VULNERABILITY THROUGH DIET-INDUCED KETOSIS

Abstract Enhanced lipid metabolism contributes towards carcinogenesis at multiple levels, serving as a "gain of function" in several cancers, including glioblastoma. Seemingly paradoxical to these findings, pre-clinical investigations have demonstrated anti-tumor activity mice fed high fat/low carbohydrate ketogenic diet (KD), both alone and combination with conventional therapy. Therefore, we sought define mechanistic underpinnings contributing this apparent disconnect. Consistent previous reports, KD independent potent synergy RT when tested an aggressive glioblastoma orthotopic model. To provide window into metabolic consequences glioblastoma, performed global metabolomic profiling on tumors serum from standard KD. Although ketosis was confirmed, no change glucose observed mice, suggesting presence/absence carbohydrates might not be the activity. Interestingly, profound intra-tumoral changes were intracranial KD, accumulation unsaturated fatty acids emerging central node. Intriguingly, recapitulating findings culture conditions vitro, polyunsaturated acid linoleic anti-proliferative activity, decreased clonogenic capacity, GBM cells, vivo findings. This cultured monounsaturated oleic acid. Through series investigations, went identify storage homeostasis lipotoxicity associated free played contributory role differential different classes acids. Importantly, PUFA-rich modified showed antitumor our preliminary investigation. These studies collectively reaffirm that enhanced brain may serve exploitable vulnerability through modification.