Abstract 3911: High-throughput screening of patient-derived HCC organoids for drug discovery

Abstract

Abstract Current in vitro models of primary liver cancer insufficiently recapitulates the tumor heterogeneity and pathophysiology of the original patient's tumor. This significantly hinders translational studies and often leads to the high rate of clinical trial attrition and poor patient response. Recent technological advances in organoid culture methods have been reported to overcome these limitations. Our group has successfully established 3 patient-derived HCC tumor organoids that closely recapitulate the patient's pathophysiology. Conventional short-term monolayer culture of the same 3 tumors as well as 3 non-tumoral adjacent liver and 3 normal liver organoids were established and compared with 5 HCC cell lines from ATCC for their drug response profiles. Subsequent drug screening was performed using a panel of 100 drugs, of which 70 are FDA-approved for either HCC or other cancers, as well as 30 pipeline compounds targeting frequently mutated pathways in HCC. We found that our screening pipeline could achieve robust z' scores and reproducible data points with technical and biological replicates. Principal component analysis of Total Area under curve (AUC) values show distinct and progressive changes between Normal Liver, Non-tumoral adjacent liver, and Tumor organoids. Upon comparison with HCC cell lines Hep3B, HepG2, Huh7, SNU398 and PLC5, we found HCC patient-derived short term cultures, particularly organoids have more diverse drug sensitivity profiles and may be a better indicator of patient heterogeneity. Interestingly, FDA-approved drugs for HCC such as Regorafenib show high sensitivity and tumor specificity to ATCC cell lines (ATCC vs Normal liver P=0.00017***), but this specificity was reduced and lost in patient-derived 2D cultures (P=0.045*) and organoids (P=0.895), respectively. This may explain the observed hepatotoxicity observed in HCC patients and warrant further investigation of more targeted ways of treating HCC. Citation Format: Alissa Michelle Go Wong, Winnie Cheung, Maggie Wong, Aikha Wong, Helena Lam, Zhe Zhang, Matthew Man, Hui Chen, David Close, Paul Johnston, Anthony Chan, Paul Lai, Joseph Kwong, Nathalie Wong. High-throughput screening of patient-derived HCC organoids for drug discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3911.