PROJECT SUMMARY/ASTRACT Gastric cancer (GC) is a leading cause of cancer incidence, mortality, and survival disparities in Latinos, the largest and youngest U.S. minority and the largest racial/ethnic group in the UCaTS states of California and Texas. When compared to non-Latino whites (NLW), GC incidence and mortality is ~>2-fold higher in Latinos. Indeed, among all cancer types, GC is the malignancy with the highest disparity ratio among Latinos. Latinas have a 2.6-fold higher GC mortality compared to NLW women, while Latino men are at a 2.1.-fold higher risk of dying when diagnosed with GC relative to NLW men. Despite this high GC burden and the fact that most gastric tumors carry “druggable” mutations, only three targeted therapies have been approved for GC. As part of our ongoing UCaMP (University of California Minority Patient-Derived Xenograft Development and Trial) minority- focused PDTC, we have shown that most GC molecular subtypes in Latinos carry druggable mutations and that they are particularly enriched in tumors carrying multiple and complex genome alterations in PI3K/AKT/mTOR, CDK, WNT, and RTK/RAS pathway genes. Over half of Latino tumors have mutations in multiple genes in these and other pathways. Because ~35% of Latino GCs have dual/concurrent PI3K and CDK pathway alterations, we will initially focus our studies using these two pathways but will aim to expand to other type of tumors with co- mutated pathways. This project aims to develop a body of pre-clinical and mechanistic data that will help address Latino GC disparities, and that will be necessary for the establishment of minority-focused clinical trials of targeted therapies. As part of our NCI-funded UCaMP PDTC, our UCaTS research team has already successfully created 55 patient-derived GC models, with ~60% of the models from Latinos. We have also shown that Latino PDXs are responsive to dual treatments with PI3K inhibitors (PI3Ki) and CDK inhibitors (CDKi) and have identified a model with PIK3CA hotspot mutations with an exquisite response to the PIK3i taselisib. Using our UCaTS infrastructure of six comprehensive cancer centers in California and Texas, our goal in the next cycle of our U54 study is to establish an additional 60 GC models, all from minorities, and to work on the following aims: i) To evaluate GC patient-derived models for identifying efficacious drug combination in tumors with multiple pathway alterations; ii) To understand the mechanisms of response to taselisib in PIK3CA mutant tumors and; iii) To evaluate the effect of genetic ancestry in response to chemotherapies and targeted therapies in Latinos. Through these studies we will develop effective drug combinations that can be rapidly translated into minority- focused clinical trials for gastric cancer patients.