Protein synthesis inhibitor omacetaxine is effective against hepatocellular carcinoma
Ling Li1, Gilad Halpert2, Michael G Lerner3
1Division of Gastroenterology and Hepatology and.
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.
Insights
Omacetaxine shows promise in treating hepatocellular carcinoma (HCC), the deadliest liver cancer. This study utilized patient-derived organoids to identify omacetaxine as an effective small molecule for HCC, paving the way for clinical trials.
Area of Science:
- Oncology
- Drug Discovery
- Cancer Biology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally.
- High costs and limited preclinical models hinder the development of new HCC therapeutics.
- Effective small molecule drug screening platforms are crucial for advancing HCC treatment.
Purpose of the Study:
- To develop and implement novel patient-derived organoid (PDO) and patient-derived xenograft (PDX) models for high-throughput drug screening in HCC.
- To identify effective small molecules for HCC treatment using these preclinical models.
- To elucidate the mechanism of action for promising drug candidates in HCC.
Main Methods:
- Implementation of patient-derived organoid (PDO) and patient-derived xenograft (PDX) models for drug screening.
- High-throughput screening of small molecules in HCC PDOs.
- Serial dilution experiments to determine drug efficacy at various concentrations.
- Mechanistic studies to investigate drug action on protein synthesis and molecular targets.
- High-throughput expression screening to identify molecular targets.
Main Results:
- Omacetaxine, an FDA-approved drug, was identified as a highly effective small molecule in HCC PDOs.
- Omacetaxine demonstrated efficacy at nanomolar concentrations across a cohort of 40 HCC PDOs.
- Mechanistic studies revealed omacetaxine inhibits global protein synthesis, particularly short-half-life proteins.
- Key oncogenes, including PLK1, were identified as molecular targets of omacetaxine.
Conclusions:
- Omacetaxine is effective in preclinical models of hepatocellular carcinoma (HCC).
- The study provides a proof-of-principle for using PDOs and PDX models in drug discovery for HCC.
- Omacetaxine's mechanism involves inhibition of protein synthesis, targeting key oncogenes like PLK1.
- Clinical trials evaluating omacetaxine for HCC patients are warranted.
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