Abstract 1071: Studying the ability of retinoids to inhibit growth of CRC cells based on their retinoid pathway genotype

Abstract

Abstract Colorectal cancer (CRC) tumorigenesis arises through acquisition of mutations in a colonic stem cell (SC) that transforms it into a cancer stem cell (CSC). There are no curative treatments for advanced CRC because CSCs appear to be resistant to chemotherapy and/or radiation. Because all-trans retinoic acid (ATRA) is a highly effective and often curative treatment for acute promyelocytic leukemia patients, we conjecture that retinoids may be an efficacious treatment for CRC. Retinoic acid (RA) is a metabolite of vitamin A which is known to induce differentiation of SCs and inhibit cell proliferation. Our goal is to discover how to therapeutically target human CRC CSCs using the differentiation-inducing effects of retinoid agents. Our previous study on the RA metabolizing enzyme aldehyde dehydrogenase (ALDH) shows that ALDH marks normal and malignant colonic SCs and that RA signaling mainly occurs through colonic ALDH+ SCs. Hypothesis: The ability of retinoid agents, ATRA, 9-cis retinoic acid, 13-cis retinoic acid and Liarozole, to induce differentiation of CSCs depends on the RA pathway genotype according to mutations in RA signaling components in CRC cells. Indeed, our bioinformatics analysis shows that many RA pathway genes are overexpressed and often mutated in CRC. We have also evaluated the ability of the different RA ligands to inhibit cell growth and induce differentiation using a panel of CRC cell lines that have specific RA signaling mutations. Further investigation of RA signaling mechanisms that regulate colon SCs and how dysregulation contributes to the SC overpopulation that drives CRC growth should provide insight into strategies for designing new SC-targeted therapies for CRC. Citation Format: Victoria O. Hunsu, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Studying the ability of retinoids to inhibit growth of CRC cells based on their retinoid pathway genotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1071.