Objectif Prostate cancer (PCA) is a genetically heterogeneous disease. Advances in targeted hormonal therapy (second generation anti-androgens) have led to more effective management of castration-resistant prostate cancer (CRPC). Despite these highly potent drugs, disease recurs with new genomic and epigenetic alterations. In this ERC proposal, I will leverage my expertise in cancer genomics and a new computational methodology to unravel the landscape of lethal PCA, with a focus on determining the Achilles’ heel of these aggressive tumours. In Aim 1, I will take advantage of DNA sequencing data from over 1000 patient-derived tumour samples and use highly innovative mathematical algorithms to create a detailed evolution chart for each tumour and identify driver events leading to CRPC. After nominating candidate drivers, we propose testing 10 using in vitro gain- and loss-of-function validations experiments (i.e. CRISPR/Cas9, shRNA, and Tet-On assays) in PCA cell lines using migration, invasion, and cell cycle as readouts. In Aim 2, I will focus on genomic events that occur in recalcitrant CRPC, positing that genetic alterations occurring prior or secondary to treatment harbour clues into resistance. In vitro validations will be performed on the top 10 biomarkers. In Aim 3, I will nominate synthetic lethality combinations by mining CRPC genomic data taken from Stand Up 2 Cancer CRPC clinical trials. I will prioritize mutually exclusive genomic alterations in genes for which approved drugs exist. The top 5-10 candidates will be validated in a prostate lineage-specific manner. In summary, this ERC proposal will leverage my many years of expertise in PCA genomics and emerging public and private CRPC datasets to uncover driver mutations that will enhance our understanding of recalcitrant CRPC. Successful completion of this study should lead to novel treatment approaches for CRPC and to a computational model that may transform our approach to evaluating other cancers. Champ scientifique medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesclinical medicineoncologyprostate cancermedical and health sciencesclinical medicineoncologybladder cancermedical and health sciencesmedical biotechnologygenetic engineeringgene therapynatural sciencesbiological sciencesgeneticsDNA Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-CoG-2014 - ERC Consolidator Grant Appel à propositions ERC-2014-CoG Voir d’autres projets de cet appel Régime de financement ERC-COG - Consolidator Grant Institution d’accueil UNIVERSITA DEGLI STUDI DI TRENTO Contribution nette de l'UE € 1 996 428,00 Adresse VIA CALEPINA 14 38122 Trento Italie Voir sur la carte Région Nord-Est Provincia Autonoma di Trento Trento Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 996 428,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire UNIVERSITA DEGLI STUDI DI TRENTO Italie Contribution nette de l'UE € 1 996 428,00 Adresse VIA CALEPINA 14 38122 Trento Voir sur la carte Région Nord-Est Provincia Autonoma di Trento Trento Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 1 996 428,00