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- W3162401559 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." @default.
- W3162401559 created "2021-05-24" @default.
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- W3162401559 date "2021-06-22" @default.
- W3162401559 modified "2023-10-08" @default.
- W3162401559 title "Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma" @default.
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- W3162401559 doi "https://doi.org/10.1172/jci.insight.138197" @default.
- W3162401559 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8262474" @default.
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- W3162401559 hasPublicationYear "2021" @default.
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