Objectif HER2 is a membrane receptor tyrosine kinase overexpressed in 30% of breast tumors and results in an aggressive clinical course. Anti-HER2 therapies including monoclonal antibodies (trastuzumab) and small-molecule tyrosine kinase inhibitors (lapatinib) are active and have improved survival of patients with HER2 overexpressing breast cancer. However, the emergence of primary or acquired resistance to these agents limits their efficacy. We have previously identified mechanisms of resistance to anti-HER2 therapies such as the co-expression of a truncated form of HER2 that correlates with trastuzumab resistance or the presence of downstream oncogenic mutations of PI3K or PTEN loss that result in resistance to lapatinib . Not surprisingly, PI3K/mTOR inhibitors overcome lapatinib resistance in the later example. Building on our results to date, this proposal is aimed at identifying novel mechanisms of resistance to anti-HER2 agents and to devise therapeutic strategies to revert it. To uncover such mechanisms, we have generated cancer cells with acquired resistance to lapatinib or trastuzumab by continuous exposure to increasing concentrations of these agents. We will perform genome wide screens, including shRNA libraries, gene expression and SNPs arrays, to discover candidate genes responsible for decreased sensitivity to anti-HER2 agents. To overcome anti-HER2 therapy resistance we will study several therapeutic strategies, such as combinations of different anti-HER2 compounds and the use of alternative agents targeting downstream/parallel pathways. Among the novel targeted therapies, we plan to study the use of PI3K, Akt, CDK2 and Hsp90 inhibitors, for which we will also start resistance-screens. It is anticipated that any promising preclinical leads will stimulate trial design and conduct for subsequent evaluation and confirmation in the clinic. Champ scientifique medical and health sciencesclinical medicineoncologybreast cancernatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsgenomes 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) Thème(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Appel à propositions ERC-2009-AdG Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON (VHIO) Contribution de l’UE € 1 666 700,00 Adresse CALLE NAZARET 115-117 08035 Barcelona Espagne Voir sur la carte Région Este Cataluña Barcelona Type d’activité Research Organisations Contact administratif Alejandro Piris Gimenez (Dr.) Chercheur principal Jose Manuel Baselga Torres (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON (VHIO) Espagne Contribution de l’UE € 1 666 700,00 Adresse CALLE NAZARET 115-117 08035 Barcelona Voir sur la carte Région Este Cataluña Barcelona Type d’activité Research Organisations Contact administratif Alejandro Piris Gimenez (Dr.) Chercheur principal Jose Manuel Baselga Torres (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
