Objectif High-grade gliomas are the most frequent type of primary brain tumor in adults. Despite optimal multi-modality treatment the disease almost always recurs, at which point median survival is less than a year. Vorinostat (suberoylanilide hydroxamic acid) is the first member of a new class of anti-cancer compounds - histone deacetylase (HDAC) inhibitors, that modulate global gene expression. The drug potentiates the anti-cancer activity of cytotoxic agents in a range of tumor types. The standard dosing schedule is low-dose drug for a long-duration. Recently ‘high-dose short-duration’ vorinostat in combination with chemotherapy has been shown to be well tolerated by subjects with colon cancer and leukemia.Radiation therapy kills cancer cells by inflicting DNA damage. Vorinostat potentiates radiation induced cell death (radiosensitization) through down-regulation of DNA repair. Clinical trials assessing combined low-dose vorinostat and radiation are in progress. In this proposal we investigate short-duration very high-dose vorinostat in combination with hypofractionated radiation therapy (RT) for recurrent glioma.Method: A phase I dose-escalation trial for subjects with recurrent glioma scheduled to undergo surgery followed by RT. Vorinostat will be administered both before surgery and post-operatively concurrently with RT. Tissue removed at surgery (exposed to vorinostat) will be compared with previously resected tumor from the same patient at the time of original diagnosis (unexposed to vorinostat), enabling analysis of how the drug modulates the levels of DNA repair enzymes. The overall goal of the proposal is to demonstrate the feasibility and biological rationale for this combined modality approach in recurrent glioma, laying the groundwork for a subsequent randomized phase II trial. Exploratory analyses will attempt to correlate response with DNA repair enzyme expression – a possible stratification factor in future trials. Champ scientifique medical and health sciencesclinical medicinesurgerynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologycolorectal cancermedical and health sciencesclinical medicineoncologyleukemianatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2011-CIG - Marie-Curie Action: "Career Integration Grants" Appel à propositions FP7-PEOPLE-2011-CIG Voir d’autres projets de cet appel Régime de financement MC-CIG - Support for training and career development of researcher (CIG) Coordinateur MEDICAL RESEARCH INFRASTRUCTURE DEVELOPMENT AND HEALTH SERVICES FUND BY THE SHEBA MEDICAL CENTER Contribution de l’UE € 100 000,00 Adresse TEL HASHOMER SHEBA MEDICAL CENTER 52621 Ramat Gan Israël Voir sur la carte Type d’activité Research Organisations Contact administratif Eve Keret (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée