Objectif Patients suffering from triple-negative breast cancer (TNBC) have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents and lack drug targets such as estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2. Insufficient knowledge on the biology of this specific breast tumor type and its heterogeneity hinder the identification of potential novel drug targets. Lethality enhancer screening is an ideal approach to identify new drug targets in tumors with specific genetic aberrations. We plan to adapt this concept of synthetic lethality by anticipating that while TNBC cells confer resistance to available anticancer drugs, specific knock down of particular genes by RNA-interference (RNAi) may result in a synergistic cell killing. Another important aspect of our approach is that we will concentrate in our screens on the top 500 candidate genes shown to be crucial in TNBC for cellular processes. The genes will be prioritized by Bayesian network analysis on prior knowledge on clinical TNBC from our own extensive genomics and proteomics studies, the literature, next generation sequencing efforts, and databases listing drugability of targets. We will employ RNAi-based knock down of drugable targets in 22 cell lines to reveal genes essential for drug resistance in TNBC. In addition to 2D cultures, screens will also be applied to 3D cultures, which are thought to better reflect the in vivo situation. The most effective combinations for each TNBC subtype will further be functionally investigated in vitro and in vivo to unravel the molecular nature of the synthetic lethality. Finally, translational studies will be performed to establish the potential clinical relevance of the identified targets/pathways in large numbers of human TNBC and non-TNBC tumors on tissue microarrays. It is expected that the newly designed (combination) therapies result in a decline in TNBC mortality and reduction of healthcare costs. Champ scientifique natural sciencesbiological sciencesgeneticsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicssocial sciencessociologydemographymortalitymedical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemedical and health sciencesclinical medicineoncologybreast cancer Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Appel à propositions ERC-2012-ADG_20120314 Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM Contribution de l’UE € 1 829 673,41 Adresse DR MOLEWATERPLEIN 40 3015 GD Rotterdam Pays-Bas Voir sur la carte Région West-Nederland Zuid-Holland Groot-Rijnmond Type d’activité Higher or Secondary Education Establishments Contact administratif Auritima Jorge Ribeiro (Ms.) Chercheur principal Johannes Albert Foekens (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (3) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM Pays-Bas Contribution de l’UE € 1 829 673,41 Adresse DR MOLEWATERPLEIN 40 3015 GD Rotterdam Voir sur la carte Région West-Nederland Zuid-Holland Groot-Rijnmond Type d’activité Higher or Secondary Education Establishments Contact administratif Auritima Jorge Ribeiro (Ms.) Chercheur principal Johannes Albert Foekens (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée UNIVERSITEIT LEIDEN Pays-Bas Contribution de l’UE € 569 044,15 Adresse RAPENBURG 70 2311 EZ Leiden Voir sur la carte Région West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Type d’activité Higher or Secondary Education Establishments Contact administratif Ton Brouwer (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Pays-Bas Contribution de l’UE € 96 384,00 Adresse PLESMANLAAN 121 1066 CX Amsterdam Voir sur la carte Région West-Nederland Noord-Holland Groot-Amsterdam Type d’activité Research Organisations Contact administratif Henri Van Luenen (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée