Abstract 5776: Advancing a screening platform with panels of patient-derived organoid models for drug discovery and development

Abstract

Abstract High-throughput screening (HTS) offers the potential to rapidly evaluate the activities of anticancer single agents and combinations in many types of cell-based tumor models; however, successful translation of the findings to patients requires tumor models with high biological relevance. The National Cancer Institute’s Patient-Derived Models Repository (PDMR, https://pdmr.cancer.gov) continues to develop a collection of highly characterized patient-derived organoid models representing a variety of cancer types including rare and recalcitrant malignancies and tumors from patients of diverse ancestry. More than 230 publicly available organoid models are undergoing characterization of their suitability for incorporation into HTS panels based on their recovery from cryopreservation, reproducible growth and expansion capacity, and assay performance metrics in a 384-well format with a CellTiter-Glo 3D viability endpoint. Organoid models with suitable characteristics are being screened with a library of 166 FDA-approved oncology drugs (https://dtp.cancer.gov/organization/dscb/obtaining/default.htm). Over a 7-day period, the organoids are exposed to five concentrations of each drug with a 1-log dilution series ranging from 0.01 µM to 100 µM. The concentration-response profiles of patient-derived organoids will provide reference data for the organoid screen and will eventually include data from all approved and most investigational oncology agents (approximately 1,000 small molecules). NCI-60 cell lines were screened as monolayers in a 384-well format with a CellTiter-Glo viability endpoint after a 3-day exposure to the same oncology drug concentrations. Both monolayer and 3D tumor models were tested using a custom designed fully automated screening system and data analysis software platform. A comparison of the FDA-approved drug responses of a panel of 3D colon cancer organoids and a corresponding panel of 9 colon carcinoma NCI-60 cell lines elucidated similarities and differences attributable to the assay methodologies as well as the tumor model characteristics, such as the presence of a BRAF V600E variant or other clinically relevant genetic alterations (APC, ARID1A, BRCA2, etc.). As the characterization of PDMR organoid models for HTS continues, these pharmacological datasets will be made available as a resource for the cancer research community. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Annamaria Rapisarda, Eric Jones, Curtis Hose, Erik Harris, Petreena S. Campbell, Mariaestela Ortiz, John Connelly, Nanda Mahashetty, Thomas Silvers, Zahra Davoudi, Penny Sellers Brady, Tiffany Nikirk Rohrer, Julie Grams, Karen Martin, Patricia Ramsey, Lori Bowles, John R. Britt, Ralph E. Parchment, Thomas S. Dexheimer, Beverly A. Teicher, James H. Doroshow, Nathan P. Coussens. Advancing a screening platform with panels of patient-derived organoid models for drug discovery and development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5776.