Objectif Systemic treatment of advanced cancers is hampered by the development of drug resistance. To prevent resistance, my laboratory has in the past used functional genetic screens to discover several “synthetic lethal” drug combination therapies, which has resulted in 8 clinical trials to date, including one global phase 3 study. In this program, I propose a new approach to the treatment of cancer, which is not based on combinations of drugs, but rather on the sequential treatment with drugs. In a first treatment step, cells will not only be induced to stop dividing, but they will at the same time acquire a major new vulnerability that is subsequently targeted with a second drug that selectively kills cells having the newly acquired vulnerability. To accomplish this, we will take advantage of recent observations that the cellular senescence response is not only a property of primary cells, but can also be triggered in advanced cancers. Such senescent cells have dramatic changes in gene expression, chromatin structure and metabolism that we will exploit for their selective eradication.Using chemical compound libraries and loss-of-function genetic screens in cancer cells harboring a reporter gene that is activated selectively in senescent cells, we will search for genes and compounds that induce senescence in cancer cells. This will lead to the identification of compounds and/or signaling pathways whose inhibition induces senescence in cancer cells. We will also use chemical compound screens to find tools to selectively kill senescent cancer cells. We will use the targets and compounds identified in this program to test the in vivo efficacy of this “one-two punch” consecutive therapy approach: the first to induce senescence in cancer cells, the subsequent therapy to eradicate the senescent cells. We present here preliminary data that the concept of sequential drug treatment can be effective, which serves as an important proof of concept for the strategy proposed here. Champ scientifique medical and health sciencesbasic medicinepharmacology and pharmacydrug resistancemedical and health sciencesclinical medicineoncology Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-2017-ADG - ERC Advanced Grant Appel à propositions ERC-2017-ADG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Contribution nette de l'UE € 2 478 750,00 Adresse PLESMANLAAN 121 1066 CX Amsterdam Pays-Bas Voir sur la carte Région West-Nederland Noord-Holland Groot-Amsterdam Type d’activité Research Organisations 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 € 2 478 750,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Pays-Bas Contribution nette de l'UE € 2 478 750,00 Adresse PLESMANLAAN 121 1066 CX Amsterdam Voir sur la carte Région West-Nederland Noord-Holland Groot-Amsterdam Type d’activité Research Organisations 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 € 2 478 750,00