Abstract 3087: The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids

Abstract

Abstract Resistance to chemotherapy drugs is a well-documented issue inhibiting the treatment of a wide variety of cancers. Colorectal cancer (CRC) is the third most common neoplasm worldwide and has the third highest mortality rate. However, the longtime gold-standard FOLFOX chemotherapy regimen, consisting of 5-FU and Oxaliplatin, results in only 70% survival rates in Stage 3 CRC patients, worse in Stage 4. More recent targeted therapies have marginally improved on this number, but the fact remains that CRC represents a highly heterogeneous neoplasm and resistance to standard chemotherapeutic regimens poses a significant barrier in treating this devastating disease. There is an immediate need to better understand how this resistance arises. We hypothesize that a small number of cells with high phenotypic plasticity (HPP) are able to remain dormant during the initial chemotherapy treatment then reenter the cell cycle to cause recurrence and metastasis months or even years after treatment has concluded. Patient-derived organoids (PDOs) are a recently developed ex vivo model that allows for the study and extensive characterization of such HPP cell populations that may be found in patient tumors. We are developing and expanding various PDO populations to examine them genotypically and phenotypically on the single-cell level through RNA sequencing and high throughput imaging, respectively. By identifying these HPP cell populations, we then discover drugs that prevent the development of drug-resistant subpopulations. In the long term, we use our tumor heterogeneity profile to develop models that predict the responsiveness of tumors, including their drug-resistant HPP subpopulations, to well-documented and clinically used oncology drugs, streamlining treatment and improving survival outcomes. Citation Format: Julia M. Morris, Curtis A. Thorne. The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids [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 3087.