Incretin Mimetics for Intercepting Obesity-Related Cancers: Effects and Underlying Mechanisms - PROJECT SUMMARY Obesity is a risk and progression factor for ≥13 cancers including, including endometrial cancer (EC, the most common obesity-related cancer in women), and colorectal cancer (CC, the most common obesity-related cancer in men). Incretin mimetics, which are agonists at one or more satiety-related receptors, can induce sustained weight loss. Limited epidemiological and preclinical data on these medications suggest potential for preventing obesity-related cancers, albeit via unclear mechanisms. We propose to test the novel central hypothesis that incretin mimetics offer protection from common obesity-related cancers via interacting mechanisms involving direct effects on CD8+ T cells as well as systemic effects on diet-regulated hormones, particularly leptin. We will leverage rigorous, complementary lines of research (preclinical models of obesityassociated cancers and a medically supervised human weight loss cohort) with state-of-the-art approaches, robust informatics data integration, and an accomplished transdisciplinary team to (a) identify immunologic, molecular, metabolic and anticancer effects of semaglutide v tirzepatide, 2 FDA-approved incretin mimetics for weight loss that differ in their anti-obesity effectiveness, across mouse models of EC and CC; (b) extend in multiple preclinical models our preliminary finding that CD8+ T cells play a central mechanistic role in TZP’s anticancer effects; and (c) establish concordance of incretin mimetic-associated anticancer effects between mouse models and women at high risk for EC undergoing medically supervised weight loss. Three specific aims are proposed to test our hypothesis: 1. Determine the effects of SEM v TZP v vehicle on phenotypic, immunologic, and molecular features and tumor outcomes in mouse models of obesity-driven EC and CC; 2. Establish the interacting roles of CD8+ T cells and leptin in SEM v TZP’s anticancer effects in models of EC and CC; and 3. Determine the effects of SEM and TZP on phenotypic and molecular features systemically and in the uterus of women at risk of EC undergoing medically supervised weight loss. The proposed studies in mice and humans will clarify whether, and how, 2 incretin mimetics, differing in their receptor targets and antiobesity effectiveness, inhibit EC development and progression in individuals. The proposed studies propose the use of vertebrate animal models in parallel with human studies because the mechanistic effects of incretin mimetics on obesity-associated tumor development, systemic metabolism, leptin signaling, and CD8⁺ T-cellmediated immunity cannot be adequately interrogated in humans alone, or replicated using non-animal systems such as cell culture or organoids. Mouse models are essential to enable controlled manipulation of diet, obesity status, pharmacologic exposure, and longitudinal tissue analyses across the full course of tumorigenesis, while also providing translationally relevant physiologic and immune responses that closely parallel those observed in humans.
