Objective 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. Fields of science 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) Topic(s) ERC-AG-LS7 - ERC Advanced Grant - Diagnostic tools, therapies and public health Call for proposal ERC-2012-ADG_20120314 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM EU contribution € 1 829 673,41 Address DR MOLEWATERPLEIN 40 3015 GD Rotterdam Netherlands See on map Region West-Nederland Zuid-Holland Groot-Rijnmond Activity type Higher or Secondary Education Establishments Administrative Contact Auritima Jorge Ribeiro (Ms.) Principal investigator Johannes Albert Foekens (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (3) Sort alphabetically Sort by EU Contribution Expand all Collapse all ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM Netherlands EU contribution € 1 829 673,41 Address DR MOLEWATERPLEIN 40 3015 GD Rotterdam See on map Region West-Nederland Zuid-Holland Groot-Rijnmond Activity type Higher or Secondary Education Establishments Administrative Contact Auritima Jorge Ribeiro (Ms.) Principal investigator Johannes Albert Foekens (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data UNIVERSITEIT LEIDEN Netherlands EU contribution € 569 044,15 Address RAPENBURG 70 2311 EZ Leiden See on map Region West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Activity type Higher or Secondary Education Establishments Administrative Contact Ton Brouwer (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Netherlands EU contribution € 96 384,00 Address PLESMANLAAN 121 1066 CX Amsterdam See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Research Organisations Administrative Contact Henri Van Luenen (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
