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  3. A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism

A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism

  • bioRxiv. 2024 Jul 23:2024.07.19.604377. doi: 10.1101/2024.07.19.604377.
Omid Hajihassani,  Mehrdad Zarei,  Asael Roichman,  Alexander Loftus,  Christina S Boutros,  Jonathan Hue,  Parnian Naji,  Jacob Boyer,  Soubhi Tahan,  Peter Gallagher,  William Beegan,  James Choi,  Shihong Lei,  Christine Kim,  Moeez Rathore,  Faith Nakazzi,  Ishan Shah,  Kevin Lebo,  Helen Cheng,  Anusha Mudigonda,  Sydney Alibeckoff,  Karen Ji,  Hallie Graor,  Masaru Miyagi,  Ali Vaziri-Gohar,  Henri Brunengraber,  Rui Wang,  Peder J Lund,  Luke D Rothermel,  Joshua D Rabinowitz,  Jordan M Winter
PMID: 39211182 DOI: 10.1101/2024.07.19.604377
Abstract

Pancreatic Cancer is the third leading cause of Cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse Cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against Cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic Cancer Models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

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