Abstract 4684: Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library

Abstract

Abstract Background: Despite recent treatment advances, malignant pleural mesothelioma (MPM) is an aggressive, recalcitrant malignancy. Currently, the 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. Therapeutic and diagnostic advances in DPM are hindered by a paucity of well-annotated preclinical models which can faithfully recapitulate the complex genomic interplay of the disease. Methods: We established a library of patient-derived xenografts (PDX) from patients with DPM. We performed multi-omic analyses on available PDX and patient samples to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA-sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months. 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: Triparna Sen. Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4684.