Targeting insulin to improve endometrial cancer

Insulin and insulin-like growth factor stimulate the growth of the endometrial mucosa by binding cell surface receptors that activate the phosphatidylinositol-3 kinase (PI3K) signaling pathway. PI3K hyperactivity is sufficient to initiate carcinoma in the uterine epithelia, where this signaling pathway promotes proliferation by activating several intracellular targets, including AKT and mTOR. Enhancement of the PI3K signaling pathway dominates the genetics of human endometrial cancer. Mutations in PIK3CA , encoding the p110a subunit of PI3K, and loss of function mutations in PTEN , a molecular off switch for the PI3K activity, are among the most frequently mutated genes in endometrial cancer. Although this high mutational burden suggests druggable targets, pharmacological inhibition of the PI3K pathway has had limited clinical outcomes. Our group has previously demonstrated that hyperinsulinemia, a clinical biomarker of endometrial cancer, limits the efficacy of PI3K inhibitors in mice and that systemic insulin can be reduced by feeding mice a very low carbohydrate (ketogenic) diet (VLCD). The combination of VLCD and PI3K inhibition can abolish tumor growth in mouse models of cancer, but the relationship between PI3K inhibition and the dysregulation of systemic glucose homeostasis has yet to be resolved in endometrial cancer. To evaluate the effects of systemic insulin on endometrial cancer growth and the efficacy of PI3K inhibition we established clinically relevant endometrial cancer xenografts via patient-derived organoids. In this study, we demonstrate that hyperinsulinemia is a modifiable factor that limits the efficacy of PI3K inhibition in endometrial cancer. By employing diazoxide and canagliflozin, pharmacological agents that counteract hyperinsulinemia, we can decrease insulin levels in the tumor while enhancing the apoptotic response to the PI3K inhibitors copanlisib and alpelisib. Additionally, we show that ketogenic diet reduces systemic insulin and improves efficacy of PI3K inhibition in xenograft models of endometrial cancer. These findings have significant implications for ongoing clinical trials of PI3K pathway inhibitors and suggest a method for increased treatment efficacy in cancer patients.