Objectif Hairy Cell Leukemia (HCL), a chronic B-cell neoplasm, is initially sensitive to chemotherapy with purine analogs, but ~40% of patients eventually relapses and becomes less responsive to these drugs. Furthermore, purine analogs may cause myelotoxicity, immune-suppression and severe opportunistic infections. Therefore, molecularly-targeted less toxic drugs are highly desirable in HCL. However, its low incidence and the initial efficacy of purine analogs has made HCL an orphan in the world of cancer research and has spoiled the academic and industrial interest in developing better treatments for this disease. But recently we identified the V600E activating mutation in the BRAF kinase as the key genetic lesion of HCL (similar to BCR-ABL1 in chronic myeloid leukemia). Orally available specific BRAF inhibitors (e.g. Vemurafenib) have in the meantime showed remarkable efficacy in melanoma patients harboring the BRAF-V600E mutation, although resistance to such drugs eventually develops in this malignancy through reactivation of MEK (the downstream target of BRAF). The ground-breaking objective of this project is to introduce for the first time in HCL, by means of phase-2 investigator-driven pilot clinical trials, the concept of BRAF and/or MEK inhibition as an oral, non chemotherapy-based, entirely out-patient, genetics-driven and rationally designed treatment strategy, first in patients with active disease despite (or severe toxicity from) previous chemotherapy with purine analogs, and then, potentially, in the frontline setting. In comparison to melanoma, deeper and longer effect of BRAF inhibition may be expected in HCL, due to its much lower genetic complexity and proliferation rate. Anyway, potential mechanisms of resistance will be searched for to identify other genes recurrently mutated or aberrantly expressed in HCL patients developing resistance to BRAF inhibition (if any), and the clinical feasibility of combined BRAF and MEK inhibition will be addressed. Champ scientifique medical and health sciencesclinical medicineoncologyskin cancermelanomanatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologyleukemia 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-CG-2013-LS7 - ERC Consolidator Grant - Diagnostic Tools, Therapies and Public Health Appel à propositions ERC-2013-CoG Voir d’autres projets de cet appel Régime de financement ERC-CG - ERC Consolidator Grants Institution d’accueil UNIVERSITA DEGLI STUDI DI PERUGIA Contribution de l’UE € 2 000 000,00 Adresse PIAZZA DELL UNIVERSITA 1 06123 Perugia Italie Voir sur la carte Région Centro (IT) Umbria Perugia Type d’activité Higher or Secondary Education Establishments Chercheur principal Enrico Tiacci (Dr.) Contact administratif Marco Bazzoffia (Dr.) 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 UNIVERSITA DEGLI STUDI DI PERUGIA Italie Contribution de l’UE € 2 000 000,00 Adresse PIAZZA DELL UNIVERSITA 1 06123 Perugia Voir sur la carte Région Centro (IT) Umbria Perugia Type d’activité Higher or Secondary Education Establishments Chercheur principal Enrico Tiacci (Dr.) Contact administratif Marco Bazzoffia (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
