Abstract LB-169: Asbestos and anthelmintics: Repurposing drugs to prevent mesothelioma in high-risk populations

Abstract

Abstract The purpose of this study is to address the rising mortality rates in mesothelioma by using repurposed drugs in a chemoprevention setting. An initial screen of 100 repurposed agents at clinically relevant concentrations was conducted across three mesothelioma cell lines using AlamarBlue assays. Having identified the top three individual and combinatorial treatments, analysis of cell-cycle and apoptosis response to these drugs was used to corroborate the findings of the initial screen. As a more representative disease model a mouse PDX was developed from a human biphasic mesothelioma, and furthermore, primary tissue obtained, both of which we have used for explant experiments to assess the efficacy of the top treatments in a more realistic and translational model. As BAP-1 mutations are highly frequent in both acquired and spontaneous mesotheliomas, a CRISPR generated knock-out cell-line will model early-stage disease, and MET-5A mesothelial cells to assess normal cell response. The three top agents, comprising zinc acetate, niclosamide, and colchicine, have proven consistently efficacious in reducing mesothelioma cell-line viability by up to 72.59% individually and 93.55% in combination. Congruent results are provided by annexin V-FITC and FACS experiments which indicate treatments induce cell cycle alterations and apoptosis. Furthermore, FACS analysis of PDX explants also shows increased apoptosis of up to 27.0% in response to 24-hour treatment of two combined drugs. Importantly, the PDX still retains original histopathological features of the human tumour, making it an important foundation for further ex vivo and ultimately in vivo study. Initial results are promising and indicate that several repurposed agents significantly reduce survival and increase death of mesothelioma both in vitro and ex vivo. Mesothelioma, being predominantly caused by long-term asbestos exposure, has been under-researched due to an overreliance on the disuse of asbestos. As such, there is no effectual treatment and average survival remain static at under one year. However, following initial asbestos exposure, a 50-year latency precedes diagnosis, which offers an opportune window for a prevention strategy. Using the CRISPR-BAP-1-knockout cell-line to model early-stage disease, we hope to translate the top candidate into a primary prevention setting. However given the increasing frequency of late stage mesothelioma diagnoses, there is also a tangible need for secondary and tertiary prevention. Repurposed drugs, which offer long term safety and side effect profiles, as well as requiring less temporal and financial investment, allow expedited translation of any potential top candidate into clinic. Through further mechanistic analyses in in vitro and ex vivo cancer models, we hope to identify a single agent or combination that could significantly impede mesothelioma progression and ultimately reduce mortality. Citation Format: Bethan G. Rogoyski, Ankur Karmokar, Sameena Khan, Hong Cai, Farhat L. Khanim, Sara Busacca, Lynne Howells, Dean A. Fennell, Anne L. Thomas, Karen Brown. Asbestos and anthelmintics: Repurposing drugs to prevent mesothelioma in high-risk populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-169.