Combination Of Epigenetic, Differentiation And Dna Damaging Agents Induce Tumor Cell Death And Stem Cell Depletion In Breast Cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAThe histone deacetylase inhibitor, entinostat, is a new-generation epigenetic drug, which has recently demonstrated notable clinical efficacy when used in combination with standard therapy. Retinoids induce differentiation in various types of stem cells. However, its delivery to patients is challenging because of its rapid metabolism. Also, epigenetic changes in the retinoic acid receptors often render cancer cells retinoid-resistant. We have shown that a combination of entinostat, all-trans retinoic acid (ATRA) and doxorubicin causes significant regression of xenografts of triple negative breast cancer (TNBC) cells and investigated the mechanism underlying the effectiveness of this combination therapy. Combinations of entinostat, retinoic acid and doxorubicin were optimal in causing tumor regression in triple negative breast cancer xenografts. Gene expression analysis of treated TNBC cells identified genes most effectively reprogrammed by entinostat and doxorubicin (ED) combination therapy. These genes are involved in cell cycle arrest, inflammation and differentiation, which are related to better survival outcome in patients. Entinostat sensitizes the cells to doxorubicin-induced growth arrest, resulting in increased apoptosis and necrosis. Adding ATRA to ED regulated interferon genes and members of the cancer/testis antigens (CTA) and tripartite motif (TRIM) family of proteins and induces inflammation in nude mice. Entinostat/ATRA/dox therapy was most effective to target breast cancer stem cells (BCSC) in limiting dilution assays of growth in mammary fat pads. The epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate cellular proliferation and differentiation mediates the epigenetic differentiation effect. Patient-derived distant metastases responded to entinostat/ATRA/dox therapy in culture. Thus, the combination therapy may have significant effects in decreasing both local and metastatic growth in breast cancer, especially in decreasing recurrence by targeting breast cancer stem cells.Citation Format: Vanessa F. Merino, Nguyen Nguyen, Helen Sadik, Soonweng Cho, Leslie Cope, Xian C. Zhou, Zhe Zhang, Qian Chen, Duojia Pan, David L. Huso, Syed Ali, Christina Adams, Balazs Győrffy, Saraswati Sukumar. Combination of epigenetic, differentiation and DNA damaging agents induce tumor cell death and stem cell depletion in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4231. doi:10.1158/1538-7445.AM2015-4231