Abstract 6516: Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) remains among the most lethal cancers. PDAC can take up to 15-20 years to develop from the occurrence of the first initiating mutational event, which opens the opportunity for intervention and prevention strategies. In particular, nutritional interventions could provide an avenue to prevent or slow down pancreatic carcinogenesis, since certain diets such as high-fat diets (HFD) have shown to promote it. On the other hand, ketogenic diets (KD), characterized by a high fat and very low carbohydrate content, have gained attention for their anti-tumor and anti-inflammatory potential. However, the role of a KD in the onset and progression of PDAC is still unknown. In this project, we investigated the impact of both a HFD and a KD on late-stage pancreatic carcinogenesis. For this purpose, we used an animal model of pancreatic cancer carrying a pancreas-specific oncogenic KRASG12D mutation [LSL-KRASG12D; P48+/Cre; (KC mice)]. On average, KC mice develop PDAC at 12-15 months of age, so they are a valuable tool to study late-stage carcinogenesis. We hypothesized that a HFD would accelerate PDAC progression while a KD would slow it down. To test our hypothesis, 6 months-old male and female KC mice (n=18/group) were randomized and fed, either a control diet (CD), a HFD, or a KD for 6 months and then euthanized at 12-months of age to evaluate pancreatic cancer incidence and progression. At 12-months of age, HFD-fed mice had significantly higher body weight compared to the other two groups. Moreover, KD-fed mice had significantly higher levels of blood ketone bodies, with lower levels of glucose and serum insulin levels, when compared to KC mice fed a HFD. However, after 6 months on the diets, no significant differences in pancreas weight nor in PDAC incidence were observed across all diet groups. Of note, male KC mice experienced double the PDAC incidence rates (55%) than female KC mice (27%), irrespectively of the group. In addition, no significant differences among the groups were observed in RAS/RAF/ERK and PI3K/AKT/mTOR pathways, known to be associated with cancer proliferation. In summary, despite the improvement in insulin and increases in ketone bodies, consumption of a strict KD failed to improve late-stage pancreatic carcinogenesis in mice. Citation Format: Tarek Bacha, Natalia Cortez Penso, Maria Rodriguez, Brian Hong, Gerardo Mackenzie. Comparison study between a ketogenic diet and a high-fat diet on pancreatic cancer incidence in mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6516.