Abstract 4192: In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography

Abstract

Abstract Intestinal mucositis is a prevalent adverse event associated with antineoplastic therapies, such as chemotherapy, which still lacks a targeted and effective treatment regimen. The difficulty in preclinical prediction and prevention of drug-induced intestinal mucositis is attributed to the intricate underlying mechanisms of its onset and the broad spectrum of patient-specific responses to chemotherapeutic agents. Advancements in regenerative medicine have enabled the generation of intestinal organoids from adult stem cells, serving as a personalized model to emulate disease pathology and simulate individual drug responses. Various imaging techniques are employed to evaluate the responses of the organoids to pharmacological agents, but the inherent complexity of their three-dimensional (3D) architecture poses significant challenges in organoid imaging. These challenges are exacerbated by the standard preparation processes for imaging, including fixation and staining, which do not allow for the observation of dynamic, real-time effects of drugs on living organoids. In this study, we focused on meticulously examining the histopathological alterations in small intestinal organoids subjected to chemotherapeutic agents that induce mucositis, specifically 5-fluorouracil and irinotecan. Employing holotomography, a label-free real-time 3D imaging technology, we were able to visualize the destructive processes affecting the intestinal organoids, including the breakdown of the epithelial lining, the exfoliation of dead cells, and the alteration of the villus/crypt structure. Furthermore, we propose a novel methodology for quantifying the viability of intestinal organoids. This quantification is essential for assessing the extent of damage caused by the chemotherapeutic agents and for determining the maximum drug concentrations that can be deemed safe for use, thereby minimizing the risk of inducing mucositis while maintaining therapeutic efficacy. These results provide new insights into the toxic mechanisms of chemotherapeutic drugs and highlight the importance of using organoid models in drug safety evaluation throughout the development phase. Citation Format: Mahn Jae Lee, Jaehyeok Lee, Weisun Park, Geon Kim, Hye-Jin Kim, YongKeun Park. In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4192.