Objective Oncogenic signalling networks display a remarkable degree of plasticity. Despite only a limited number of alterations in oncogenes and tumour suppressor genes in most tumours, the majority of targeted therapeutics (monoclonal antibodies and small-molecule kinase inhibitors) does not strongly improve the survival of cancer patients and suffers from the rapid development of resistance. The rising number of targeted drugs in clinical use inhibits only a very limited number of protein targets (largely kinases). Consequently, most intracellular non-kinase oncoproteins remain untargeted. We have previously established the use of small engineered antibody mimics, termed monobodies, to potently and specifically target intracellular protein-protein interactions mediated by the SH2 domains of oncogenic kinases and phosphatases. Expression of SH2-targeting monobodies resulted in the inhibition of signalling and oncogenesis of these oncoproteins. Here, we aim at developing monobody binders to 10 key intracellular oncoproteins for which no chemical inhibitors exist and testing their activity in cancer cells. To enable a possible clinical translation of monobody-based therapeutics, we will develop methods to deliver monobody proteins into cells, including cell-penetrating peptides, bacterial toxins and biocompatible nanocarriers. 'Mirror-image' monobodies, composed of D-amino acids, will be developed and tested to increase intracellular and plasma stability and to limit immunogenicity. The developed monobodies and delivery systems are planned to be tested in mouse cancer models. Our goal is to establish monobodies as novel class of intracellular protein-based therapeutics. We hope to kick off their use beyond basic research tools towards possible applications in cancer patients. This innovative endeavour uses state-of-the-art protein engineering techniques to address a central problem in cancer medicine and may provide a ground-breaking new approach to target cancer. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesclinical medicineoncology Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-CoG-2015 - ERC Consolidator Grant Call for proposal ERC-2015-CoG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution PHILIPPS UNIVERSITAET MARBURG Net EU contribution € 1 419 148,41 Address BIEGENSTRASSE 10 35037 Marburg Germany See on map Region Hessen Gießen Marburg-Biedenkopf Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 419 148,41 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all PHILIPPS UNIVERSITAET MARBURG Germany Net EU contribution € 1 419 148,41 Address BIEGENSTRASSE 10 35037 Marburg See on map Region Hessen Gießen Marburg-Biedenkopf Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 419 148,41 ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE Participation ended Switzerland Net EU contribution € 576 906,59 Address BATIMENT CE 3316 STATION 1 1015 Lausanne See on map Region Schweiz/Suisse/Svizzera Région lémanique Vaud Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 576 906,59
