Abstract 7108: Leveraging race-informed biological models for disparities research in colorectal cancer

Abstract Background: Non-Hispanic Black (NHB) patients have a 20% higher incidence of colorectal cancer (CRC) and a 40% higher CRC mortality than non-Hispanic white (NHW) patients. Disparities may be explained by socioeconomic variables (such as smoking or obesity) and access to health care. However, the role of potential biological differences remains unclear. Patient-derived organoid models (PDOs) provide an ideal model system to study biological differences and avoid confounding clinical variables by focusing on the genomic, phenotypic and functional differences in CRC cells ex vivo. There is currently a lack of patient-derived preclinical models from NHB populations. We aim to build a public biobank of NHB patients with detailed clinical annotation, chemosensitivity and biological characterization, examining intrinsic tumor cell states in different genomic backgrounds as potential variables in CRC outcomes. Methods: PDOs were established from surgically resected primary and metastatic CRC samples from NHB and NHW patients, processed through enzymatic digestion and filtration, and cultured in Matrigel in human intestinal stem cell (HISC) media. Genomic features of the corresponding patients were analyzed using the MSK-IMPACT targeted DNA sequencing assay. We assessed the responses of NHB and NHW PDOs to FOLFOX chemotherapy through drug sensitivity assays with 5-FU:oxaliplatin (concentration of 25:1). Dose-response curves were fitted using the two-parameter logistic regression model to calculate median IC50. After dissociation into single cells, PDOs were cultured in HISC and Base (media without intestine-specific growth factors) conditions for 11-14 days and analyzed by bulk RNA-sequencing to capture phenotypic differences associated with canonical intestinal (less aggressive) and non-canonical (more aggressive) cell states. Results: We aim to establish a biobank of 10 NHB and 10 comparative NHW patients with similar clinicogenomic profiles. To date, 12 PDOs derived from 5 NHB (3 primary and 2 metastasis samples) and 7 NHW (2 primary and 4 metastasis samples) patients are characterized with further PDO collection ongoing. Four samples with KRAS missense mutations were present across the NHB and NHW patient groups (NHB: 80%, NHW: 57%). IC50 of five NHB and five NHW PDOs revealed no significant differences in sensitivity to FOLFOX (median IC50 NHB: 70.3uM; median IC50 NHW: 59.92uM). ssGSEA scores derived from bulk RNA-seq data of five PDOs, comparing three NHB and two NHW patients, exhibited greater variation across lines than within racial groups, with no significant differences between NHB and NHW patients. Conclusions: Ongoing work is focused on building a larger cohort for wider comparative characterization. The future completed biobank will become a public resource for scientists to access racially diverse PDOs for drug testing and further biological characterization. Citation Format: Xiang Han, Stefanie Gerstberger, Kathleen Luckett, Francesco Cambuli, Jaeyop Lee, Andres Rettig, Ahmed Mahmoud, Jonathan Bermeo, Asha Saxena, T.Peter Kingham, William Jarnagin, Philip Paty, Martin Weiser, Michael D’Angelica, Rona Yaeger, Julio Garcia-Aguilar, Francisco Sanchez-Vega, Karuna Ganesh. Leveraging race-informed biological models for disparities research in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7108.