Abstract 6805: A ketogenic diet sensitizes pancreatic cancer to metabolic therapies

Abstract Background: Pancreatic cancer is the third leading cause of cancer-related death in the United States, and current chemotherapy options provide limited benefit. Recent studies have shown that a ketogenic diet (KD) can exert anti-tumor effects by reprogramming tumor metabolism and exposing new therapeutic vulnerabilities1. Efforts to target glutamine metabolism—an essential pathway in many cancers—have shown promise in preclinical models but have not translated into significant clinical success. Methods: A ketogenic diet was administered to mice, along with a normal diet in control mice. Pancreatic cancer xenografts were monitored for growth and harvested for biochemical analyses. Tumors were analyzed for metabolites and histone modification by LC/GC-MS and for oxidative stress by measuring the levels. Result: Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation is in response to increased tumor dependence on glutamine-mediated anaplerosis to compensate for reduced glucose availability. Additionally, we examined the impact of a ketogenic diet on redox homeostasis and found that tumors from ketogenic-diet-fed mice exhibited a marked increase in ROS levels. This redox imbalance provides further rationale for combining TCA-cycle inhibition with ROS-inducing agents to amplify metabolic and oxidative stress in PDAC tumors. We demonstrate that combining glutamine metabolism inhibitors, such as CB839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Moreover, the combination of ivosidenib and a ketogenic diet caused a synergistic rise in intratumoral ROS and yielded a 50% survival benefit in treated mice. Conclusion: Together, these findings demonstrate that a ketogenic diet exposes a metabolic and redox vulnerability in PDAC by increasing reliance on glutamine-driven anaplerosis and elevating intratumoral ROS. Exploiting this state with targeted metabolic inhibitors—alone or in combination with ROS-inducing agents—produces potent anti-tumor responses and highlights a promising therapeutic strategy for pancreatic cancer. Citation Format: Omid Hajihassani, Asael Roichman, Jacob A. Boyer, Michael MacArthur, Ricardo Cordova, Priyashree Sunita, Goutam Dey, Parsa Rezvani, Alexander Loftus, Christina Boutros, Jonathan Hue, Parnian Naji, Nimat Manzoor, Anika Buch, Hallie J Graor, Joshua D. Rabinowitz, Jordan M. Winter. A ketogenic diet sensitizes pancreatic cancer to metabolic therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6805.