Background: A third of patients with solid malignancies develop brain metastases. Expected overall survival is 4-7 months depending on age, performance status, and extracranial disease. Standard treatment is controversial; however, the majority of patients receive wholebrain radiation therapy at some point. Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved HDAC inhibitor, has been demonstrated to radiosensitize tumor cells in vitro, as assessed by both radiation-induced DNA damage and clonogenic cell survival (Munshi et al. Molecular Cancer Therapeutics 5, 1967-1974, 2006). We have shown that vorinostat downregulates key genes involved in double-strand DNA repair (Rad50, Rad51, XRCC2, XRCC3, XRCC6), as assessed by quantitative PCR. This suggests that the drug’s mechanism of radiosensitization is epigenetic coordinated inhibition of the DNA repair process. We hypothesize that the combination of vorinostat with whole-brain radiation therapy will be both safe and efficacious.

American Society of Clinical Oncology (ASCO) 46th Annual Meeting June 4-8, Chicago, IL.

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