Vorinostat Inhibits Brain Metastatic Colonization in a Model of Triple-Negative Breast Cancer and Induces DNA Double-Strand Breaks

Abstract

Purpose: As 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 Design: The 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. Results: Following 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. Conclusions:We 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. (Clin Cancer Res 2009;15(19):6148-57) Significant advances have been made in the treatment of primary breast cancer; one of the unfortunate complications of this progress is an increase in the incidence of brain metastases (reviewed in refs. 1, 2). Combinations of cytotoxic and targeted therapies have afforded metastatic breast cancer patients' clinical responses or stable disease, but the poor penetration of these drugs into the brain and leptomeninges creates a "sanctuary site" for recurrence. With an increased number of metastatic breast cancer patients having stable disease or responding to treatment systemically when they develop brain metastases,

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…Concerning metastases, another study of an in vivo model of TNBC has reported that SAHA treatment is involved in the induction of DNA double-strand breaks suppressing brain metastatic colonization by 62% (54). Further studies that combine SAHA with DNA active drugs or radiation are needed in order to investigate thoroughly their actions against metastases.…”

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

“…For example, as shown in Table 3, preclinical models from the Steeg and other laboratories suggest that a number of compounds (e.g., pazopanib and vorinostat, among others) can prevent brain metastases even if they are not efficacious in the "treatment" setting (i.e., drug dosing begun only after macrometastases are allowed to form, with tumor shrinkage as an endpoint; refs. 29,31,90,91). In a HER2 overexpressing model, Zhang and colleagues have recently demonstrated a profound prevention of experimental metastasis by the combination of lapatinib and the Src inhibitor saracatinib (32).…”

Heading in a New Direction: Drug Permeability in Breast Cancer Brain Metastasis

“…Palmieri and colleagues have recently used this model to evaluate the novel histone deacetylase inhibitor vorinostat (11). This research suggests a new definition of targeted therapy: not only targeting a particular molecule, but also having the capability of targeting a specific metastatic site.…”