(P13-044-23) Consumption of a Ketogenic Diet Enhanced Vitamin B6 Metabolism Pathway but Did Not Inhibit Tumor Growth in an Obesity-Associated PDAC Mouse Model

Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate due to ineffective treatments. Obesity, which can be the result of western dietary patterns, is a recognized risk factor for PDAC. Thus, developing effective weight management strategies is essential to decrease obesity, and potentially mitigate PDAC risk. The high-fat, low-carbohydrate ketogenic diet (KD) promotes weight loss and is a promising therapeutic strategy in some cancer preclinical models by altering tumor metabolism. Therefore, we hypothesize the KD will disrupt cancer metabolism, promote weight loss, and delay tumor growth in obesity-associated PDAC.

Methods: C57BL/6 mice were fed an obesogenic high-fat diet (HFD) for 15 weeks to induce obesity, after which were randomized to a control diet (CD), a KD, or continued in the HFD for 7 weeks. After, mice were orthotopically injected with mouse KRas^G12D/Trp53^−/−/PDX-1-CRE (mKPC) cells containing the firefly luciferase gene. Tumor growth was monitored through In Vivo Imaging System. Body weight, glucose tolerance tests, and ketone body (KB) measurements were performed at different timepoints. Tumors metabolomics were analyzed by Liquid Chromatography Mass Spectrometry (LC-MS).

Results: Mice gained weight after 15 weeks of an obesogenic diet. Mice fed a KD and a CD significantly lost weight after the diet interventions. Mice fed a KD maintained increased KB concentrations and increased glucose tolerance after tumors. However, none of the dietary interventions decreased tumor growth. Tumors showed significant enrichment in metabolic processes, such as, vitamin B6 metabolism in mice fed a KD compared to HFD group.

Conclusions: Although the KD induced weight loss and altered tumor metabolism, it was insufficient to decrease tumor growth in an obesogenic PDAC mouse model. However, vitamin B6 has shown antitumor properties in other mouse models. Understanding the availability and functions of vitamin B6 metabolism induced by a KD, could indicate its potential as an intervention for obesity-associated genetically engineered mouse models of PDAC.

Funding Sources: National Institute of Health, USDA Training Grant, James Comprehensive Cancer Center, and OSU Interdisciplinary PhD program in Nutrition