Abstract 3021: Understanding the effects of a ketogenic diet against pancreatic cancer

Abstract

Abstract With an overall survival of less than 3%, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related death in the U.S. at its advanced stages. With the most promising therapeutics, the overall survival after a stage IV PDAC diagnosis is only at 11.1 months. The marginal effects of current therapeutics emphasize the importance of developing new approaches to treat PDAC. In a wide range of cancer subtypes, a ketogenic diet has shown encouraging effects as combination therapy. However, the underlying anti-tumorigenic pathways involved in this diet alone are still not well understood. The ketogenic diet’s core elements and direct physiologic effects (ketone bodies, fatty acids, low glucose, low insulin levels) potentially alter PDAC biology that span from redox homeostasis to mitochondrial metabolism, and epigenetic modifications. We hypothesized that in carefully controlled in vitro and in vivo experiments, KD components delay growth of PDAC. Additionally, we hypothesize that understanding the underlying drivers of the anti-tumor effects of a ketogenic diet could be leveraged into the rational design of combination therapies that augment these anti-tumor effects. We show that in the subcutaneous mouse model of PDAC, tumor growth is markedly delayed under ketogenic diet restrictions Furthermore, in PDAC cell culture models, we observed anti-cancer effects when the ketogenic diet core elements are isolated. Specifically, fatty acids and ketone bodies inhibit PDAC cell growth, particularly under high glucose conditions. These effects are somewhat attenuated under low glucose, suggesting that these elements result in competing effects on PDAC cells (i.e., support some pro-survival pathways while inhibiting others). Future studies seek to better delineate the mechanistic impact of the principal ketogenic diet elements on metabolic pathways with a focus on mitochondrial metabolism, as well effects on epigenetic signaling. Citation Format: Omid Hajihassani, Ali Vaziri-Gohar, Mehrdad Zarei, Jonathan Hue, Helen Cheng, Anusha Mudigonda, Erryk Katayama, Hallie Graor, Jordan Winter. Understanding the effects of a ketogenic diet against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3021.