PROJECT SUMMARY Obesity and diabetes are associated with increased risk of developing endometrial cancer (EC) and increased risk of death. Obese EC patients have a 9-fold higher mortality from all causes compared with non- obese patients. Thus, it seems logical that interventions to combat obesity, insulin resistance and cardiometabolic health may improve EC outcomes. High-intensity interval training (HIIT) is a time-efficient exercise strategy in which short intense exercise periods are interspersed with recovery periods. HIIT requires as little as 10 minutes of exercise per session (2 times a wk) and rapidly improves cardiorespiratory fitness and other metabolic outcomes in as few as 2 wks. In overweight/obese adults, we found that 3 wks of HIIT results in significant improvements in markers of cardiovascular health, triglycerides, lipids and insulin. In addition, we have demonstrated that HIIT is feasible in pre-bone marrow transplant patients, with 70% completing 6 wks of training prior to transplant. Collectively, these preliminary data support the feasibility and applicability of HIIT in obese EC patients. We have explored the chemotherapeutic potential of the anti-diabetic drug metformin in EC. In the LKB1fl/flp53fl/fl EC mouse model, diet-induced obesity led to a doubling of tumor size and increases in lipid biosynthesis. Metformin showed increased efficacy against EC in obese vs. lean mice and reversed the detrimental metabolic effects of obesity in ECs. In our phase 0 clinical trial of obese EC patients, short-term metformin treatment reduced proliferation and decreased expression of targets of the insulin/mTOR pathway within the ECs. Metformin had beneficial effects on lipid pathways in responders to treatment. In a similar phase 0 clinical trial, we propose to assess HIIT as a metabolic treatment of EC. We hypothesize that HIIT will reduce tumor growth and improve the metabolic milieu of EC patients, specifically through inhibition of insulin and lipid pathways. To explore this hypothesis, we will conduct a randomized pre-operative HIIT intervention in obese EC patients. Women who undergo surgical staging for EC will receive a 3-wk home-based HIIT exercise treatment versus standard of care (no HIIT intervention) that will be completed twice weekly. The goal of this trial is to assess the impact of HIIT on EC proliferation and related metabolic pathways by comparing pre-intervention endometrial biopsies to post-intervention hysterectomy specimens. In parallel, we will delineate the interplay of HIIT on the cardiometabolic health of the EC patients via a comprehensive assessment of cardiovascular and metabolic biomarkers of HIIT response that includes traditional (VO2peak, BMI, HgBA1C, fasting insulin/glucose, lipids) and novel (metabolomic profiling) biomarkers. This innovative approach will lead to a greater understanding of the feasibility and initial effects of HIIT in EC treatment. This will be the first trial of HIIT in EC and will provide the underlying biological framework for future clinical trials of HIIT as a metabolic targeted strategy in obesity-driven EC.