Abstract PD01-05: A Combination of HDAC Inhibitor Entinostat (MS-275), All Trans Retinoic Acid (ATRA) and Chemotherapy Drug(s) Causes Regression of Established Xenografts of Triple Negative Breast Cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is a subgroup of breast cancer that rapidly develops resistance to chemotherapy. Currently, TNBC patients are treated with anthracycline and taxane-based regimens. These treatments result in some improvements in the clinical outcomes; however, they are associated with poor prognosis. Also, endocrine therapies are ineffective since the tumors do not express the estrogen receptor. Recent studies have shown that histone deacetylase (HDAC) inhibitors could reverse the epigenetic profile of some genes, including ER, EGFR, and RAR≥2. We have recently shown that treatments that combine the HDAC inhibitor, Entinostat (MS-275), with the aromatase inhibitor, Letrozole, result in regression of xenografts of MDA-MB-231 breast cancer cells. Since RAR≥2 is re-expressed as well, we reasoned that combining epigenetic therapy using MS-275, with differentiation therapy using a RAR≥2 agonist (ATRA) will provide an effective combination of drugs against TNBC. We also examined possible potentiation of anticancer activity of these agents by low nontoxic doses of chemotherapy (doxorubicin and paclitaxel). In vitro, human TNBC cell lines, MDA-MB-231, HCC 1143, SUM159, SUM149 and BT20 responded significantly better to the triple combination compared to the drugs used singly or in combination with MS-275. Upon treatment, re-expression of the silenced RAR≥2 and downstream effectors was observed in the cell lines in vitro and in tumor xenografts of MDA-MB-231 cells. Subcutaneous tumor growth in immunodeficient mice was strongly inhibited (10/14 significant regression) using a combination of MS-275, ATRA and low dose Doxorubicin, compared to the drugs administered singly or in combination with MS-275. No significant weight loss was observed in any of the groups. This combination was then used to treat tumor xenografts of SUM159, another TNBC cell line, and gave a promising result. Furthermore, combination of MS-275, ATRA, and a clinical dose of Paclitaxel can effectively inhibit growth of MDA-MB-231 and SUM159 cells. These results suggest that combination of HDAC inhibitor and RAR≥2 agonist with low dose chemotherapy has the potential to be an effective treatment against TNBC. This study provides encouraging new information for a nontoxic, and novel combination of drugs which could be effective against TNBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-05.