The Isoform Selective Histone Deacetylase Inhibitor Entinostat Is Active in Primary Human Triple-Negative Breast Cancer Models.

Abstract

Abstract Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an oral, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Previous studies have a) established the anti-proliferative activity of entinostat in the triple negative cell line model MDA-MB-231 b) shown that entinostat induces expression of ERα and c) that entinostat is synergistic with aromatase inhibitors to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to validate the activity of entinostat in highly predictive primary human tumor models of triple negative breast cancer.Methods: Two approaches have been taken. First, entinostat was tested in the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack ER, PR and HER2/neu expression by immunohistochemistry (IHC). Second, entinostat was tested at 5, 15, 30 mg/kg/d in two xenograft models using tissue derived directly from patient tumor resections. The breast cancer models MV4151 (from a postmenopausal patient with ductal invasive breast carcinoma) and MV4586 (from a premenopausal patient with relapsed invasive lobular breast carcinoma) were negative for ERa protein, however still positive for ERa mRNA. Both xenograft tumors did not express ERb. The tumor doubling times in nude mice were between 10 and 30 days. Both tumors are HER-2 negative (determined by IHC).Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 µM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested with IC50's ranging from 10nM to 270nM which are within the clinically achievable concentrations of entinostat. Two of the breast tumors that were most sensitive to entinostat (IC50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat inhibited (IC50 10-270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. < 50% growth inhibition at 2.45 µM). For the xenograft studies, at the time of writing, dose response data in the MV4151 model has demonstrated tumor growth inhibition by entinostat at the 15 and 30 mg/kg/d administered orally with no apparent weight loss. Ongoing experiments for which data will be presented include dose response in MV4586 as well as combinations with tamoxifen and fulvestrant in both xenograft models.Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors in human primary tumor models. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1146.