Abstract A064: High-throughput organoid drug screening to identify molecular vulnerabilities in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that typically presents at the advanced or metastatic stage. Although some patients achieve partial responses with chemotherapy, most tumors progress rapidly and become resistant to therapy. Finding targeted therapy for PDAC remains a major challenge due to the therapeutic intractability of the four major drivers (KRAS, TP53, CDKN2A, SMAD4), and the diversity in secondary alterations driven by genomic instability. We hypothesize that this genomic complexity exposes unique molecular vulnerabilities in each patient which may be uncovered by phenotypic screening. Patient derived organoids are a novel 3-D cell culture model which can reliably expand tumors ex vivo and recapitulate genomic, transcriptomic, and drug response characteristics of the patient. Most organoid work has focused on predicting patient response to standard chemotherapy or a small number of targeted therapies, but to date there has been no effort to systematically profile a large number of agents with integrated genomic and transcriptomic data. This will allow us to define the molecular basis of patient-specific drug vulnerabilities and identify biomarkers for drug repurposing and discovery specific to PDAC. To define the functional genomic landscape of drug response in PDAC, we optimized a high-throughput drug screening platform for rapid drug profiling in organoid models with matched WGS and RNAseq. Retrospective screening of 2935 FDA-approved and investigational drugs in a cohort of 58 primary and metastatic organoids identified 799 drugs with cytotoxic activity in at least one organoid. 600 drugs were cherry-picked to enrich for diverse mechanisms of action and dose-response curve validation was performed. Drug sensitivity profiles were highly organoid-specific, and all organoids had unique sensitivities when responses were compared across the cohort. Integration of functional and molecular profiling revealed known gene-drug associations such as MDM2 inhibitor activity in TP53 wildtype organoids, but also identified novel associations such as anagrelide sensitivity in an organoid with high PDE3A expression, which has recently been linked to interactions between PDE3A and the poorly characterized Schlafen 12 protein. Anti-tumor activity of anagrelide validated in a xenograft model. Our work highlights the utility of patient-derived organoids for phenotypic drug screening and biomarker discovery, which we plan to investigate further in an upcoming prospective trial. Citation Format: Irene Y Xie, Zhen-Mei Liu, Karen Ng, Eugenia Flores-Figueroa, Gun Ho Jang, Amy X. Zhang, Stephanie Ramotar, Anna Dodd, Julie Wilson, Grainne M. O'Kane, Jennifer J. Knox, Steven Gallinger, Faiyaz Notta. High-throughput organoid drug screening to identify molecular vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A064.