Abstract 698: Establishing and characterizing patient derived models from racial/ethnic minority gastric cancer patients to advance cancer precision health equity

Abstract

Abstract Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. While overall incidence and mortality rates have dropped in recent decades, GC remains a significant cause of health disparities for all major US racial and ethnic minority groups (Black/African Americans, Hispanic/Latino Americans, Asian Americans, Native Hawaiians and Pacific Islanders, American Indians and Alaskan Natives), who are all at least twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites (NHW). Despite such high minority cancer burden, few FDA-approved targeted therapies are available for GC. This can be partially explained by limited availability of cancer genome data and patient-derived models from racial/ethnic minority populations, hampering gene target identification and drug efficacy studies. Our group has spearheaded the development of the University of California Minority Patient-Derived Xenograft Development and Trial Center (UCaMP) with the goal of addressing these critical issues for GC patient care. Thus far, we have characterized over 30 GC samples from racial/ethnic minorities (mGC), establishing patient-derived organoid lines (mPDOs) for more than half. Genomic analyses have revealed a significantly lower prevalence of chromosomal instability and higher prevalence of genomically stable GC tumors compared to TCGA, which consists predominantly of NHW patients. Our analyses have also identified high prevalence of alterations within the cell cycle regulation/cyclin-dependent kinase (CDK) and PI3K/AKT/mTOR (PI3K) pathways, both of which are therapeutically targetable by inhibitors already FDA-approved for other cancer types. At the individual gene level, these mGC patients demonstrate distinct patterns of somatic mutations, with fewer PIK3CA activating mutations, which is the most commonly mutated gene in the PI3K pathway among TCGA, and TP53 deleterious mutations while demonstrating significantly more deleterious mutations in the PTEN tumor suppressor gene. Indeed, when we treat our mPDOs with PI3K and CDK inhibitors, we observe significant responses in vitro. We are now generating genome-edited mPDO lines from normal gastric tissue to model specific alterations observed in our mGC cohort for functional characterization within GC pathogenesis and drug response validation. Our findings highlight an important molecular distinction of GC development in racial/ethnic US minorities, providing a rationale for alternative treatments to address GC health disparities. Citation Format: Nicole B. Halmai, Hongyong Zhang, Paul C. Lott, Ana Estrada-Florez, Ted Toal, Alexa Morales Arana, Rasika Venkatesh, Elizabeth Quino, Alma Poceros Coba, Guadalupe Carvajal, Javier Torres, UCaMP consortium, Luis G. Carvajal-Carmona. Establishing and characterizing patient derived models from racial/ethnic minority gastric cancer patients to advance cancer precision health equity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 698.