PROJECT 1: Characterizing Treatment Responses with PDX Models for gastric and liver Tumors PROJECT SUMMARY/ASTRACT Gastric cancer (GC) and liver cancer (LC) are leading causes of cancer incidence, mortality and survival disparities in Hispanic/Latino Americans (HLAs) and in Asian Americans, Native Hawaiians and Pacific Islanders (AANHPIs), which represent the largest and fastest growing U.S. minorities, respectively. When compared to non-Hispanics whites (NHW), GC and LC incidence and mortality is ~>2-fold higher in HLAs and AANHPI. These two malignancies are therefore leading causes of cancer health disparities in the country. Despite representing leading causes of mortality and representing tumor types with high numbers of ?druggable? mutations, only 4 GC and LC targeted therapies have been approved by the FDA so far. Another important gap in GC/LC research is that very limited cancer genome data from HLA/AANHPI gastric and liver tumors exist, which greatly limits target identification and the development of precision medicine in these two minorities. Our published and preliminary data analyses suggest that the source groups of HLA (Latin Americans) and AANHPI (Asians) have molecular profiles differing from those in NHWs and which could affect precision medicine strategies in U.S. minorities. The goals of this project are therefore to develop a body of genomic, pre-clinical and mechanistic data that will help address GC and LC disparities in minorities and that will be necessary for the establishment of minority-focused clinical trials of targeted therapies. With funding from the NCI, the University of California and philanthropy, our research group has already successfully implanted 10 GC patient-derived xenografts (PDX). Here, we will leverage this PDX resource and four NCI- designated comprehensive cancer centers of UCaMP (University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center) to: i) characterize tumor genomic profiles of the most common types of LC (hepatocellular carcinoma, HCC) and GC (Gastric adenocarcinoma, GAC) in U.S. patients of HLA and AANHPI ancestry, aiming at establishing the prevalence of the most common clinically relevant molecular subtypes and targets, some of which that maybe minority-specific; ii) screen patient-derived organoids for multiple drug combinations involving FDA-approved regimens for HCC and GAC and inhibitors targeting specific mutations. The most effective combinations will then be tested for in vivo tumor growth effects in PDXs from HLAs, AANHPIs and NHWs; and iii) investigate resistance mechanisms using single cell clonal analyses and isogenic cell line modeling.
