Abstract 2896: A flexible mouse model of malignant pleural mesothelioma

Abstract

Abstract Patients with advanced malignant pleural mesothelioma (MPM) have extremely limited treatment options. To develop targeted therapies necessary to radically alter the clinical course of MPM, it is important to identify oncogenic mutations and signaling pathways that drive its development and progression. About 75% of MPMs carry inactivating mutations at the NF2 locus, which encodes the FERM domain protein Merlin, and often also have deletions of the CDKN2A locus, encoding the CDK inhibitor p16 and the p53 activator ARF. Since traditional cancer therapies target dysregulated oncogenes, it is important to elucidate the pathogenically relevant proteins that are dysregulated downstream of MPM tumor suppressors. We have developed a flexible and rapid mouse model that can be used to dissect genetics of MPM, to evaluate the preclinical efficacy of novel therapies, and to provide a platform for MPM shRNA genetic screens. We injected into the pleural cavity of mice lentivirus encoding Cre recombinase and miR30-based shRNA cassettes to simultaneously deplete four of the most commonly lost proteins in mesothelioma - Nf2, p16INK4a/ARF, and BAP1. Cre recombinase deletes the Nf2 conditional allele and simultaneously activates a Luciferase reporter gene in the pleural mesothelium, allowing for bioluminescent imaging of infected cells that develop MPM tumors. Lentiviral miR30-based shRNA cassettes simultaneously deplete Ink4a/ARF and Bap1, helping to drive tumorigenesis. To evaluate MPM genetics, mice with conditional alleles for putative drivers of MPM pathogenesis (i.e. Dcaf1 and Ptk2) in addition to the Nf2 conditional allele can be injected with the virus to determine whether these genes are necessary and sufficient for MPM development or progression. Moreover, knockdown of putative MPM drivers can be easily carried out by adding corresponding shRNA cassettes to the lentiviral vector. Using these methods, we have developed a rapid genetically engineered mouse model that recapitulates human MPM and can be used to explore MPM genetics. This flexible MPM mouse model will allow us to unravel MPM genetics and help to identify novel therapeutic targets as well as provide an efficient preclinical test of these therapies. Citation Format: Jonathan Cooper, Filippo Giancotti. A flexible mouse model of malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2896. doi:10.1158/1538-7445.AM2015-2896