Abstract 6583: Systems scale characterization of malignant pleural mesothelioma to discover novel therapies

Abstract

Abstract We have built a platform integrating systems genetics and functional genomics for the discovery of therapies to eradicate residual microscopic tumor foci after surgical resection of the deadly cancer malignant pleural mesothelioma (MPM). Using our SYstems Genetics Network AnaLysis (SYGNAL) network inference pipeline we constructed a malignant pleural mesothelioma gene regulatory network to discover disease causing TFs and miRNAs regulatory interactions. We then overlaid the MPM gene regulatory network with significant hits from pooled CRISPR-Cas9 knock-out out growth functional genomics screens in low passage number MPM patient-derived cell lines. We then queried this integrated network to identify patient survival associated TFs and miRNAs that when knocked-down (siRNA) or over-expressed (miRNA mimic), respectively, are likely to have anti-proliferative effects in low passage number patient-derived cell lines. The perturbation of a majority of these TFs and miRNAs led to significantly lower proliferation in the patient-derived cell lines. Further, the expression of the regulator or its target genes should function as a biomarker(s) for whether therapy will be effective for a particular patient's tumor. We are currently working with our collaborator at the NCI to develop these siRNA and miRNAs into their existing miRNA mimic hydrogel delivery system and test them in orthotopic xenografts using the low passage number patient derived cell lines. Citation Format: Sierra F. Wilferd, Chuong D. Hoang, Christopher L. Plaisier. Systems scale characterization of malignant pleural mesothelioma to discover novel therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6583.