Unmet needs in malignat pleural mesothelioma (MPM) are the lack of early detection strategies, the intrinsic chemoresistance, the lack of biomarkers for experimental and innovative therapeutic strategies,including angiogenesis and immune modulators. The consortium has set-up a robust living biobank of MPM to explore therapeutic strategies to de-orphan MPM pathogenesis, including primary cultures, patient-derived xenografts (PDXs) and innovative 3D-immune-organoids. We hypothesize that the above biobank as well as tissue and liquid biopsies will serve as a prerequisite to lead an unprecedented multi-tasking functional effort and identify actionable pathways, therapeutic strategies and predictive biomarkers.
Aims: 1)To molecularly annotate living MPM preclinical models and patient samples (WP1,WP2, WP3,WP8); 2)To perform functional and pharmacogenomics screens in MPM preclinical models in order prioritize combination therapies for clinical testing (WP4, WP5, WP6); 3)To identify candidate predictive and prognostic biomarkers in MPM patients treated with immunotherapy and/or anti-angiogenic therapy (all WPs).
Methods: pre-existing MPM models and those generated in WP2 following approval of a joint biobanking protocol(WP1) will be subjected to –omics analyses (WP3). Drugs (WP4) and genome-wide Crispr/Cas9 libraries(WP5) will be screened in primary MPM cultures and hits validated in PDXs. Immunoorganoids will be tested ex vivo with immunotherapy and angiogenesis modulators(WP6). Selected markers from WP3 and WP6 will be tested in liquid biopsies from MPM patients treated with anti-angiogenic or immune-based therapies (WP7). Bioinformatics(WP8), data integration(WP9), and project management strategies(WP10) are in place. This project will couple molecular profiling to functional characterization of MPM models. Novel therapeutic strategies suitable for clinical testing and minimally invasive biomarkers could result in better patient management and outcome