Abstract 2168: Intermittent fasting in combination with carboplatin in a pre-clinical model of obesity-driven endometrial cancer

Abstract

Abstract Objectives: Endometrial cancer (EC) incidence and mortality continue to rise, with obesity a well-known driver of this disease. Obesity is associated with excess estrogen, hyperinsulinemia, activation of the Akt/mTOR pathway, chronic inflammation, and a heightened capacity to harvest dietary energy, all of which contribute to the development and progression of EC. Intermittent energy restriction (IER) is thought to have anti-tumorigenic benefits and has been shown to have synergistic effects with chemotherapy and hormonal therapy in various cancer types. Thus, we evaluated the anti-tumorigenic effects of a switch from high fat diet (HFD) to either IER or low fat diet (LFD) with carboplatin treatment in a mouse model of obesity-driven endometrioid EC. Methods: Lkb1fl/flp53fl/fl mice were fed either HFD or LFD starting at 4 weeks of age. At 12 weeks of age, the HFD-fed mice were randomized to three treatment groups: continuous HFD, HFD-LFD switch, and HFD-IER switch. The LFD-fed mice were continuously maintained on LFD. At 16 weeks of age, all mice were injected with AdCre into the left uterine horn to induce EC development. At 26 weeks of age, mice were treated with placebo or carboplatin (50 mg/kg intraperitoneally weekly) for 4 weeks (n=8-10 mice per group). EC incidence, tumor weight, and body weight were evaluated. EC gene expression was assessed by microarray analysis. Results: EC incidence was lowest in the HFD-IER group (~60%) and highest in the HFD group (~80%); rates were similar in the other diet groups (~75%). The continuous HFD-fed mice demonstrated a 76% increase in tumor size relative to continuous LFD-fed mice (p<0.001). At sacrifice and after carboplatin treatment, mean body weights were significantly higher (p<0.05) in the HFD group (38g) than groups receiving continuous LFD (26g), HFD-LFD switch (28g), or HFD-IER switch (21g), although mean body weights were not significantly different within diet groups between placebo and carboplatin-treated mice. In placebo-treated groups, mean tumor weights were significantly lower in mice fed continuous LFD (0.62g), HFD-LFD switch (0.60g) and HFD-IER switch (0.26g) relative to continuous HFD-fed mice (1.10 g; p<0.001). When comparing gene expression between the HFD-LFD and the HFD-IER placebo groups, genes related to cholesterol metabolism, estrogen response, and inflammation were preferentially up-regulated in the HFD-IER group. Carboplatin treatment reduced EC tumor size 42-69% across all diet groups (p<0.05); tumor size was the smallest in the HFD-IER group (0.15g) relative to mice receiving continuous HFD (0.34g), HFD-LFD (0.29g) or continuous LFD (0.34g). Conclusion: IER with carboplatin treatment may be an innovative combination treatment strategy in the management of EC, a highly obesity-driven cancer. Citation Format: Jennifer Haag, Olivia Lara, Chunxiao Zhou, Stephen D. Hursting, Victoria Bae-Jump. Intermittent fasting in combination with carboplatin in a pre-clinical model of obesity-driven endometrial cancer [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 2168.