Abstract 453: Orlistat as a novel targeted therapy for obesity-driven endometrial cancer

Abstract

Abstract Introduction: Obesity is associated with increased risk for and worse outcomes from endometrial cancer (EC). Orlistat is a weight loss medication that has been shown to be a potent inhibitor of fatty acid synthase (FAS), and FAS is known to be upregulated in ECs. Thus, we sought to investigate the anti-tumorigenic potential of orlistat in EC cell lines and a genetically engineered mouse model of endometrioid EC (LKB1fl/flp53fl/fl mouse model). Methods: Two endometrial cell lines, ECC-1 and KLE, were used. Cell proliferation was assessed by MTT assay after exposure to orlistat. Western immunoblotting was performed to evaluate the effect of orlistat on downstream targets of fatty acid metabolism. LKB1fl/flp53fl/fl mice were fed a control low fat diet (LFD; 10% calories from fat, lean group) versus a high fat diet (HFD; 60% calories derived from fat, obese group) to mimic diet-induced obesity, starting at 3 wks of age. AdCre was injected at 6 wks of age to induce invasive EC. Mice were treated with placebo or orlistat (200 mg/kg/day, IM) following tumor onset for 4 weeks (N=10 mice/group). Immunohistochemistry was performed to assess for the effect of orlistat on expression of Ki-67 (marker of cell proliferation), vascular endothelial growth factor (VEGF) and phosphorylated (p)-acetyl-CoA carboxylase (ACC). Results: Orlistat inhibited growth in a dose-dependent manner for both endometrial cell lines with a mean IC50 for ECC-1 of 88.7 uM and 145.4 uM for KLE (p<0.05). In addition, orlistat decreased expression of FAS, ACC and carnitine palmitolytransferase 1A, consistent with an inhibitory effect on fatty acid metabolism. In both the obese and lean LKB1fl/flp53fl/fl mice, treatment with orlistat resulted in decreased tumor weight/size as well as Ki-67 expression (p<0.05), but the difference was more pronounced in obese mice. Orlistat decreased tumor weight/size by 66% in the obese mice and 23% in the lean mice (p<0.05). Immunohistochemistry revealed that p-ACC and VEGF expression was higher in the obese versus lean mice at baseline (p<0.05). Orlistat reduced VEGF in the endometrial tumors of both the obese and lean mice (p<0.05) but only decreased expression of p-ACC in the tumors of obese mice (55%, p<0.05). Conclusions: Orlistat inhibited EC cell proliferation and endometrial tumor growth in an endometrioid EC mouse model, with increased efficacy in obese versus lean mice. Therefore, orlistat may be worthy of drug repurposing as an anti-tumorigenic agent in EC, with the potential added benefit of weight loss in this obesity-linked disease. Citation Format: Stephanie Sullivan, Arthur-Quan Tran, Weiya Wysham, Paola Gehrig, Chunxiao Zhou, Victoria Bae-Jump. Orlistat as a novel targeted therapy for obesity-driven endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 453. doi:10.1158/1538-7445.AM2017-453