Abstract A065: Differential sensitivity of normal and tumor organoids to targeted therapies

Abstract

Abstract Background: Advances in the culture of cells from human tissues have enabled the generation of normal and tumor organoid pairs derived from the same patient. These organoid cultures increase the scope for predicting responses to novel cancer therapeutics in patients. 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 responses beyond conventional cell viability measurements, including those associated with tumor killing, cell cycle arrest, toxicity and epithelial permeability and discriminates therapeutic and adverse responses in healthy tissue and tumor. Methods: Intestinal organoids, obtained from HUB Organoid Technology, cultured in natural extracellular matrix scaffolds 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, novel targeting antibodies and small molecules on tumor growth suppression and killing as well as function, formation and integrity of the gut epithelium, we tested a panel of normal and colorectal cancer organoids with a broad heterogeneity of mutations. 3D imaging and analysis was performed and responses in normal vs. tumor were compared. Results: High content 3D image analysis of the organoid enabled sensitive detection of treatment-induced and compound-specific morphological changes such as (inhibition of) growth, development, lumen formation, epithelial integrity and cell death. This enabled distinction between mechanisms of action and distinct effects and sensitivities in normal epithelium and tumor tissue from the same patient. Conclusion: 3D image analysis of in vitro cultured organoids represents a rapid and biologically relevant approach to test various anti-cancer-therapeutic modalities, including antibodies, antibody-drug conjugates and small molecules. Evaluating effects on healthy and tumor tissue from the same patient can give insight into potential toxicities and therapeutic window. Citation Format: Mariusz Madej, Cinthya Del Angel Zuvirie, Jara García Mateos, Leo Price, Lidia Daszkiewicz, Kuan Yan, Bram Herpers. Differential sensitivity of normal and tumor organoids to targeted therapies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A065. doi:10.1158/1535-7163.TARG-19-A065