{"doi":"10.1172/jci.insight.138197","title":"Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma","abstract":"Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.","journal":"JCI Insight","year":2021,"id":173441,"datarank":0.48283137373023016,"base_score":3.2188758248682006,"endowment":3.2188758248682006,"self_citation_contribution":0.48283137373023016,"citation_network_contribution":0.0,"self_endowment_contribution":0.48283137373023016,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":711202,"name":"Gilad Halpert","orcid":"0000-0002-5610-7347","position":1,"is_corresponding":false},{"id":711203,"name":"Michael G. 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Meltzer","orcid":"0000-0002-9131-1052","position":17,"is_corresponding":false},{"id":336125,"name":"Kiyoko Oshima","orcid":"0000-0002-3357-6247","position":18,"is_corresponding":false},{"id":268581,"name":"Laura M. Ensign","orcid":"0000-0002-6949-7911","position":19,"is_corresponding":false},{"id":236212,"name":"Joel S. Bader","orcid":"0000-0002-6020-4625","position":20,"is_corresponding":false},{"id":270206,"name":"Florin M. 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