Abstract 442: Exploring targetable pathways: Unveiling changes in tumor physiology through dietary modification by a ketogenic diet

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Abstract Background: A ketogenic diet, with high fat (90% kCal) and low carbohydrate (5% kCal) intake, induces ketosis [2], altering cancer cell carbon utilization toward the tricarboxylic acid cycle (TCA) [3]. While the overall impact on cancer growth is unclear, most literature suggests an anti-cancer effect. Our hypothesis aims to uncover pancreatic cancer cell adaptations to the ketogenic diet, revealing metabolic vulnerabilities for informed therapeutic strategies. Methods: Mice on a ketogenic or normal diet (control) underwent pancreatic cancer xenograft observation. Tumor metabolites were analyzed with LC/GC-MS, oxidative stress with NAD(P)+/NAD(P)H, and Lipid Peroxidation assays. Western blot assessed enzyme expression. In vitro studies used Seahorse FX Analyzer for mitochondrial function and PicoGreen for cell growth quantification. Ivosidenib and CB839 were used for combination therapies. Result: A ketogenic diet induces a metabolic shift in pancreatic cancer, altering nutrient and metabolite levels in diverse in vivo models. Besides the expected increase in TCA metabolites, heightened amino acid anaplerosis, particularly with glutamine and glutamate, was observed. Examination of the diet's impact on oxidative phosphorylation enzymes revealed increased BDH1 expression, aiding ketone body utilization, and upregulation of cytosolic IDH1 for antioxidant defense. Enzymes involved in glutamine uptake and conversion, like ASCT2 and GLS, showed altered expression. Simultaneously, we explored tumor microenvironment vulnerabilities, detecting a significant increase in reactive oxygen species (ROS) levels, specifically lipid peroxidation, in mice on the ketogenic diet. Given these pancreatic cancer adaptations, we hypothesized that combining therapeutics to elevate ROS levels and target the glutamine pathway would substantially impede tumor growth. To test this, we combined a ketogenic diet with an IDH1 inhibitor for antioxidant defense hindrance and a glutaminase inhibitor to impair mitochondrial function, resulting in a marked reduction in tumor proliferation compared to individual treatments. Conclusion: A ketogenic diet demonstrates a robust anti-tumor effect in various pancreatic cancer mouse models, likely arising from the diminished glucose and increased fatty acid load inherent in the diet. Metabolic adaptation towards an oxidative phosphorylation (OXPHOS) phenotype makes pancreatic cancer especially susceptible to antioxidant and mitochondrial inhibitors, as well as inhibitors of glutamine-metabolizing enzymes. Citation Format: Omid Hajihassani, Mehrdad Zarei, Soubhi Tahhan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Aya Murray, Alexander Loftus, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Jonathan Hue, Hallie Graor, Jordan Winter. Exploring targetable pathways: Unveiling changes in tumor physiology through dietary modification by a ketogenic diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 442.

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