Abstract 2083: Human normal and tumor colon organoids: a 3D high content screening platform for anticancer drug development

Abstract

Abstract Background: Recent advances in establishing organoids from human specimens have enabled further development of advanced 3D cell culture models such as normal and tumor colon organoids derived from the same patient. These organoid cultures increase the scope for predicting treatment responses in patients, enabling the testing of cancer (immune)therapies, discriminating different drug responses and flagging off-target effects. Here we present a high throughput 3D human intestinal organoid culture platform combined with high content image-based analysis. This platform allows visualization and quantification of various treatment effects on healthy and diseased gut epithelium. Methods: Intestinal organoids, obtained from HUB Organoid Technology, are cultured in natural extracellular matrix scaffolds and show gene expression patterns, differentiation and functional characteristics that closely resemble the in vivo biology. To investigate the effect of standard-of-care (SoC) treatments like 5-FU, Oxaliplatin and Irinotecan and/or (in combination with) novel targeting antibodies or other small molecules on the function, formation and integrity of the gut epithelium, we set up the following intestinal organoid test systems: 1. Colorectal cancer organoids with a broad heterogeneity of mutations for sensitive and high throughput phenotypic screening that enable accurate compound profiling and 2. Human normal vs. tumor organoid pair assays for off-target effect studies. Results: High content 3D image analysis of the organoid models enables sensitive detection of treatment-induced and compound-specific morphological changes such as (inhibition of) growth, development, lumen formation, epithelial integrity and cell death. This enables distinction between mechanisms of action and determining compound synergy. The image-based measurements can be complemented with detection of secreted factors (e.g. cytokines, chemokines) or expressed genes in response to various therapeutic compounds. Conclusion: OcellO’s advanced 3D image analysis of in vitro cultured organoids represents a rapid and biologically relevant approach to test various candidate compounds (e.g. antibodies, antibody-drug conjugates and small molecules) that can treat intestinal disorders such as Inflammatory Bowel Disease and colon cancer. This organoid technology also allows identifying potential adverse effects that can occur during in-vivo studies. Therefore, our intestinal organoid screening platform represents a significant advance on conventional in vitro models and helps bridge the translational gap between in vivo studies. Note: This abstract was not presented at the meeting. Citation Format: Mariusz Madej, Jara Garcia Mateos, Kuan Yan, Lidia Daszkiewicz, Bram Herpers, Leo S. Price. Human normal and tumor colon organoids: a 3D high content screening platform for anticancer drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2083.