Combination Therapies Targeting Insulin Signaling in Endometrial Cancer

PROJECT SUMMARY/ABSTRACT Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence and mortality rate are increasing due, in part, to the obesity epidemic. Obesity dramatically increases the risk of death from endometrial cancer, and there are a variety of systemic changes that occur in the obese state that create a milieu that favors tumor initiation and progression. One of these factors, hyperinsulinemia, has been directly implicated in the pathogenesis of endometrial cancer, and may underlie the strong association of obesity with tumor progression in this cancer type. Insulin stimulates PI3K to drive cell growth, proliferation, and anti-apoptotic pathways. Unfortunately, PI3K inhibitors have not been effective in clinical trials for endometrial cancer. Using pre-clinical models, we identified hyperinsulinemia as an acute, systemic, drug-induced adaptation that limits the efficacy of these drugs. This adverse effect can be mitigated in animal models using dietary and pharmacologic approaches that target the endocrine system. In this proposal, we will test if these strategies can be translated to clinical care using patient-derived tumor tissue, mouse xenograft models, and tissues from clinical intervention trials. We hypothesize that lowering insulin will reduce tumor markers of PI3K signaling, increase markers of apoptosis, and enhance the efficacy of PI3K inhibitors in patients with endometrial cancer. In Aim 1, we will examine the effects of a very low carbohydrate diet (VLCD) on endometrial cancer signaling and growth using patient-derived blood and tumor tissue from two ongoing clinical studies where patients are consuming a VLCD with and without a PI3K inhibitor. We will assess genetic, histologic, and biochemical markers of the Insulin/PI3K pathway, proliferation, and apoptosis. In Aim 2, we will use patient-derived xenograft models to identify novel pharmacologic strategies that lower systemic insulin levels and enhance the apoptotic response to PI3K inhibition. Specifically, we will assess the systemic insulin response and tumor growth rates in mice treated with PI3K inhibitors and 2 endocrine therapies: canagliflozin, a sodium-glucose cotransporter-2 inhibitor that prevents hyperglycemia, and diazoxide, a potassium channel activator that prevents hyperinsulinemia. Our data will provide robust pre-clinical evidence to support combination strategies that target insulin to limit the progression of endometrial cancer. If successful, these dietary and pharmacologic interventions can be rapidly implemented into clinical practice.