Obiettivo 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 Campo scientifico medical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNA Programma(i) FP6-LIFESCIHEALTH - Life sciences, genomics and biotechnology for health: Thematic Priority 1 under the Focusing and Integrating Community Research programme 2002-2006. Argomento(i) LSH-2005-2.2.0-2 - Modulation of apoptosis in cancer prevention and therapy Invito a presentare proposte FP6-2005-LIFESCIHEALTH-6 Vedi altri progetti per questo bando Meccanismo di finanziamento STREP - Specific Targeted Research Project Coordinatore INSTITUT DE RECHERCHE PIERRE FABRE Contributo UE Nessun dato Indirizzo 45, Place Abel Gance BOULOGNE Francia Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato Partecipanti (3) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto NEDERLANDS KANKER INSTITUUT Paesi Bassi Contributo UE Nessun dato Indirizzo Plesmanlaan 121 (H516; P1.011 as of 12/05) AMSTERDAM Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato ONCOTEST Germania Contributo UE Nessun dato Indirizzo Am Flughafen 12-14 D-79108 FREIBURG Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato VRIJE UNIVERSITEIT MEDICAL CENTER Paesi Bassi Contributo UE Nessun dato Indirizzo De Boelelaan 1117 AMSTERDAM Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato
