Funded by the Stuart Scott Memorial Cancer Research Fund
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Metformin is a drug used in the treatment of type 2 diabetes. Our preliminary data finds that metformin has anti-cancer activity, due to its indirect effects within the body (decreased insulin/glucose) and direct effects on EC cells through inhibiting signaling pathways involved in metabolism, including suppression of fatty acid/lipid biosynthesis. Thus, it is logical that metformin may break the link between obesity and EC and emerge as a new targeted agent for the treatment of this cancer.
Our overall goal is to assess the contribution of indirect effects (via decreasing insulin and glucose levels) and direct effects (via inhibition of metabolic pathways and blunting of fatty acid/lipid biosynthesis) of metformin to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC. We hypothesize that predictors of metformin response will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/glucose signaling and heightened fatty acid/lipid biosynthesis, and this response may differ according to race. From this work, we hope to validate metformin as an innovative treatment strategy for obesity-driven EC.