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.