Abstract 51: Multiomic profiling of patient-derived xenografts established from patients with malignant pleural mesothelioma proposes pathways associated with poor prognosis
Authors: Offin Michael , Sauter Jennifer L. , Egger Jacklyn V. , deStanchina Elisa , Poirier John T. , Zauderer Marjorie G. , Rudin Charles , Sen Triparna 
Published: June 2022

Background: Despite recent treatment advances, malignant pleural mesothelioma (MPM) is an aggressive, recalcitrant malignancy. Currently, histologic subtype (epithelioid/non-epithelioid/biphasic) is the primary prognostic factor; other potential biomarkers to guide therapeutic strategies remain elusive. Even with multimodality therapies, recurrence is high in early-stage disease. In the unresectable/metastatic setting, there are only two FDA approved regimens, both in the first line setting: cisplatin/pemetrexed and ipilimumab/nivolumab. Unfortunately, most who respond to first line treatment experience disease progression within a year. A few established MPM cell lines, with inherent limitations, provide minimal preclinical insight. The relative lack of model systems that accurately reflect MPM tumorigenesis is a barrier to therapeutic and diagnostic advances in MPM.

Methods: We developed a diverse library of 22 extensively annotated patient-derived xenograft (PDX) models from 22 patients with MPM. Multi-omic analyses including, targeted tumor next-generation sequencing by MSK-IMPACT, RNA-sequencing, and immunohistochemistry was performed. We deconvoluted the mutational landscapes, global expression profiles, and molecular subtypes of these MPM models and further compared the PDXs to MPM clinical specimens, including matched PDX and primary tumor pairs.

Results: The mutational landscapes of PDX models strongly correlated with paired tumor samples. There were some differences in CDKN2A/B mutations and relative enrichment of NF2 with fewer BAP1 alterations, the significance of which is being investigated. When compared by histological subtype, we observed an upregulation of genes involved in NOTCH and EMT signaling in the epithelioid models. Models derived from patients with shorter overall survival or poor response to platinum doublet had higher expression of WNT/β-catenin signaling, hedgehog pathway, and epithelial-mesenchymal transition signaling as well as downregulation of immune-activation pathways, including type I and II interferon signaling and inflammatory response pathways.

Conclusions: This library of MPM PDXs, the largest to date, effectively mimics human disease and provides unprecedented insight into the genomic, transcriptomic, and protein landscape of MPM. These PDX models will inform future clinical investigations and provide an important new preclinical resource.

Citation Format: Michael Offin, Jennifer L. Sauter, Jacklyn V. Egger, Elisa deStanchina, John T. Poirier, Marjorie G. Zauderer, Charles Rudin, Triparna Sen. Multiomic profiling of patient-derived xenografts established from patients with malignant pleural mesothelioma proposes pathways associated with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 51.