Repurposing Drugs for the Therapeutic Prevention of Malignant Pleural Mesothelioma

<p dir="ltr">Malignant Pleural Mesothelioma is a rare but devastating malignancy, caused by asbestos exposure. A latency period of 25-50 years following exposure provides an ideal window for therapeutic prevention. Drug repurposing offers an accelerated, cost-effective approach to developing preventive therapies with well-established safety profiles, suitable for use in healthy at-risk populations. This investigation reviews in vivo studies focused on therapeutic prevention of mesothelioma to date; highlighting the need for preclinical models suitable for preventive contexts and development of biomarkers suitable for future clinical trials. Previous unpublished work screened 97 randomly-selected drugs, identifying niclosamide for its pro-apoptotic and anti-proliferative effects in a panel of MPM cells, and significant inhibition of tumour growth in a preclinical in vivo PDSX model treated with a clinically-relevant dose of niclosamide (352.4 mg/kg/day). This investigation aims to elucidate and verify the mechanisms underlying this efficacy, using cell lines and PDSX tissue. LC-MS/MS analysis of PDSX tissue indicated inhibition of mTORC1 signalling, which was verified in MPM cell lines. Decreased expression of HSPA1A was observed in both the proteomic analysis and by immunofluorescence of PDSX tumour samples, providing mechanistic insight and a potential candidate biomarker for future research. In silico analysis using differential expression signatures from RNA sequencing of genetically engineered HAP1 cell lines (BAP1, MTAP, NF2, SETD2), and publically-available asbestos-exposed cell data, ranking the magnitude of fold change, network centrality and significance to identify the most influential differentially-regulated genes. The signatures comprised 27-130 genes and identified 243 candidate compounds across all 5 cell lines. Candidate drugs include several generic drugs with promising profiles for cancer prevention, such as desloratadine, tolazamide and tamoxifen.</p>