TOPMESO

Project Coordinator

Federico Bussolino
- Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO) - IRCCS, Head Laboratory of Vascular Oncology
- Turin - Italy

Project Partners

Luis Paz-Ares
- Hospital Universitario 12 de Octubre, Chair Medical Oncology
- Madrid - Spain
Paul Baas
- Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL)
- Amsterdam - The Netherlands

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

Malignant pleural mesothelioma (MPM) is an aggressive cancer originating from pleural mesothelial cells and mainly related to the toxic effect of asbestos with a professional or environmental origin. The latency between asbestos exposure and disease onset may be up to 50 years. Despite the ban of asbestos in many European Countries in the last 20 years, the incidence of mesothelioma is planned to increase up to 2030-2040.

Procedures for an early diagnosis are currently lacking. The diagnosis is often performed at late stages, when pharmacological treatments are the only options. However, MPM resistance to chemotherapy and immune-therapy, as well as the lack of proven efficacy of target therapy, determines a mean overall survival below 12-16 months, despite a multi-modal treatment.

TOPMESO aimed at setting-up a robust living biobank of MPM to investigate molecular and cellular features of this disease allowing the preclinical testing of innovative therapeutic strategies, which could ultimately improve the clinical outcome.

Pillars of the biobank have been primary cultures, patient-derived xenografts (PDXs) and innovative 3D-immune-organoids derived from molecularly and clinically annotated MPM specimens.

TOPMESO exploited state-of-the art cellular and molecular approaches including tridimensional multiorgan cultures, integrated omics analysis, liquid biopsy, functional screening based on genome editing and innovative imaging technologies to lead an unprecedented multi-tasking functional effort and identify actionable pathways, therapeutic strategies and predictive biomarkers.

The models and the information collected in TOPMESO have been exploited to perform functional and pharmacogenomics screens in order prioritize combination therapies for clinical testing and to identify candidate predictive and prognostic biomarkers in MPM patients treated with immunotherapy and/or anti-angiogenic therapy.

The most relevant results obtained are as follows:

1. Collections of a large clinical series for which the follow-up is underway and whose tissues have been molecularly annotated with the availability of biological material for subsequent validation of biomarkers

2.Identification of six drug categories as promising agents in MPM .

3. Establishment on in vitro 3D models from human MPM biological specimens to study the cross-talk between immune cells and cancer cells.

4. Establishment on in vivo models based on the subcutaneous implantation of human MPMs in immunocompromised mice (patient-derived xenografts) to improve MPM personalized medicine tracks.

5. Initial establishment on in vivo models based on the subcutaneous implantation of human MPMs in humanized immunocompromised mice, to have models closer to humans

6. Molecular characterization (whole genome analysis, transcriptome, epigenome) of recruited patients.

7. The relations between the Italian and Spanish partners went beyond the specific objectives of the project but led to a climate of broader understanding and co-collaboration which made it possible to create an international doctorate of "Translational Oncology" in collaboration also with the University Ersamus Rotterdam primarily focused on Thoracic tumours (https://en.unito.it/postdegree/phd/translational-oncology)