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JCI Insight. 2019 Jan 24;4(2). pii: 121490. doi: 10.1172/jci.insight.121490. [Epub ahead of print]

Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity.

Author information

1
Division of Gastroenterology and Hepatology.
2
Department of Biomedical Engineering and High-Throughput Biology Center.
3
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4
Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, James Cancer Hospital, Solove Research Institute, Health Services Management and Policy, The Ohio State University Ohio, USA.
5
Department of Oncology, Sidney Kimmel Cancer Center.
6
Departments of Cell Biology and Oncology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines. Each primary human liver cancer surgical specimen was used to generate multiple cancer organoid lines, obtained from distinct regions of the tumor. A total of 27 liver cancer lines were established and tested with 129 cancer drugs, generating 3,483 cell survival data points. We found a rich intratumor, functional (drug response) heterogeneity in our liver cancer patients. Furthermore, we established that the majority of drugs were either ineffective, or effective only in select organoid lines. In contrast, we found that a subset of drugs appeared pan-effective, displaying at least moderate activity in the majority of these cancer organoid lines. These drugs, which are FDA approved for indications other than liver cancers, deserve further consideration as either systemic or local therapeutics. Of note, molecular profiles, obtained for a reduced sample set, did not correlate with the drug response heterogeneity of liver cancer organoid lines. Taken together, these findings lay the foundation for in-depth studies of pan-effective drugs, as well as for functional personalized oncology approaches. Lastly, these functional studies demonstrate the utility of cancer organoid drug testing as part of a drug discovery pipeline.

KEYWORDS:

Drug screens; Drug therapy; Hepatology; Liver cancer; Oncology

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