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Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma
Ling Li, … , Joel S. Bader, Florin M. Selaru
Ling Li, … , Joel S. Bader, Florin M. Selaru
Published May 18, 2021
Citation Information: JCI Insight. 2021;6(12):e138197. https://doi.org/10.1172/jci.insight.138197.
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Research Article Hepatology Oncology

Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma

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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.

Authors

Ling Li, Gilad Halpert, Michael G. Lerner, Haijie Hu, Peter Dimitrion, Matthew J. Weiss, Jin He, Benjamin Philosophe, Richard Burkhart, William R. Burns, Russell N. Wesson, Andrew MacGregor Cameron, Christopher L. Wolfgang, Christos Georgiades, Satomi Kawamoto, Nilofer S. Azad, Mark Yarchoan, Stephen J. Meltzer, Kiyoko Oshima, Laura M. Ensign, Joel S. Bader, Florin M. Selaru

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Figure 1

Validation of HCC PDO and PDX models.

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Validation of HCC PDO and PDX models.
(A) H&E staining demonstrates ...
(A) H&E staining demonstrates a similar morphology/trabecular pattern in the human tissue 26-3 HCC, matched 26-3 HCC PDO, and HCC PDX26. (B–D) Clinical diagnostic immunofluorescence staining on the primary human HCC tissue, as well as on the matched PDO and PDX, demonstrates similar positivity for Hep Par1, AFP, CK7, and EPCAM. (E) Bright-field images of 3 distinct HCC PDO lines. Scale bars: 25 µM (A and E), 50 µM (B–D).

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