Objectif The failure of anti-cancer therapies generally results from locally intractable invasive growth or from the presence of metastases refractory to treatment with curative intent. A novel therapeutic strategy is to develop new anti-cancer drugs specifically targeting the invasive or metastatic phenotype of tumour cells. We propose to validate at the preclinical level a strategy that targets the critical mechanism allowing apoptosis evasion and survival of invasive or metastatic tumour cells. Anoikis is a process by which a cell detached from its resident tissue undergoes apoptosis as a result of loss of normal cell-matrix interactions. Loss of anoikis allows survival of cancer cells in abnormal microenvironments, such as tissue compartments invaded by the primary tumour, and the intravascular compartment during the metastatic process. Participant 2 has recently discovered that the BDNF receptor TrkB is a potent suppressor of anoikis and is responsible for apoptosis evasion that occurs in aggressive human tumours overexpressing TrkB (Douma et al., 2004). The aim of the present proposal is to validate TrkB as a target for new anticancer drugs, aiming to restore anoikis and thereby destroy the invasive and metastatic cancer cells. This validation will include the identification TrkB-expressing tumour cell lines amongst a collection of resected human cancers. Then, abrogation of TrkB mediated signalling will be achieved by either selective TrkB mRNA-targeting small interfering RNAs (RNAi) delivered by viral vectors, or by novel and potent small molecule inhibitors that will be designed and synthesized. The efficacy of these tools will be assessed by using anoikis-sensitive cell models and xenograft mouse models, particularly orthotopic metastasis models derived from human tumours. The mechanisms of TrkB-dependent anoikis suppression will also be investigated in order to identify additional markers for invasive and metastatic capability and novel drug target Champ scientifique medical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNA Programme(s) FP6-LIFESCIHEALTH - Life sciences, genomics and biotechnology for health: Thematic Priority 1 under the Focusing and Integrating Community Research programme 2002-2006. Thème(s) LSH-2005-2.2.0-2 - Modulation of apoptosis in cancer prevention and therapy Appel à propositions FP6-2005-LIFESCIHEALTH-6 Voir d’autres projets de cet appel Régime de financement STREP - Specific Targeted Research Project Coordinateur INSTITUT DE RECHERCHE PIERRE FABRE Contribution de l’UE Aucune donnée Adresse 45, Place Abel Gance BOULOGNE France Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée Participants (3) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire NEDERLANDS KANKER INSTITUUT Pays-Bas Contribution de l’UE Aucune donnée Adresse Plesmanlaan 121 (H516; P1.011 as of 12/05) AMSTERDAM Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée ONCOTEST Allemagne Contribution de l’UE Aucune donnée Adresse Am Flughafen 12-14 D-79108 FREIBURG Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée VRIJE UNIVERSITEIT MEDICAL CENTER Pays-Bas Contribution de l’UE Aucune donnée Adresse De Boelelaan 1117 AMSTERDAM Voir sur la carte Liens Site web Opens in new window Coût total Aucune donnée