• Diane Palmieri, Paul R Lockman, Fancy C Thomas, Emily Hua, Jeanne Herring, Elizabeth Hargrave, Matthew Johnson, Natasha Flores, Yongzhen Qian, Eleazar Vega-Valle, Kunal S Taskar, Vinay Rudraraju, Rajendar K Mittapalli, Julie A Gaasch, Kaci A Bohn, Helen R Thorsheim, David J Liewehr, Sean Davis, John F Reilly, Robert Walker, Julie L Bronder, Lionel Feigenbaum, Seth M Steinberg, Kevin Camphausen, Paul S Meltzer, Victoria M Richon, Quentin R Smith, and Patricia S Steeg.
• Women's Cancers Section, Laboratory of Molecular Pharmacology, Genetics Branch, National Cancer Institute/NIH, Bethesda, Maryland, USA. palmierd@mail.nih.gov
• Clin Cancer Res. 2009 Oct 1; 15 (19): 6148-57.

PurposeAs chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer.Experimental DesignThe 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo.ResultsFollowing systemic administration, uptake of [(14)C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52.ConclusionsWe report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation.

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