Enhanced lipid metabolism in brain tumors: an exploitable metabolic vulnerability through diet-induced ketosis.

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




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27th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, Tampa, FL, November 16-20, 2022.

American Association for Cancer Research (AACR) Annual Meeting, April 8-13, 2022, New Orleans, LA. Cancer Res. 2022 Jun 15;82(12 Suppl):17. doi:10.1158/1538-7445.AM2022-17.