Abstract 4724: Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 synergize with DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML)

Abstract

Abstract AML is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain generally poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and the DNA methyltransferase inhibitor VIDAZA™ (azacitidine) is approved by European Medicines Agency for the treatment of elderly patients with AML. Numerous clinical studies are ongoing to investigate the benefit of combining azacitidine with other investigational agents in AML. HDAC inhibitors are promising agents for the treatment of AML. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have suggested beneficial clinical activity in AML. However, the toxicity profiles of non-selective HDAC inhibitors in the combination settings limit the clinical benefit. In this work, we describe the preclinical development of highly selective HDAC inhibitors, which are hypothesized to have improved safety profiles than non-selective HDAC inhibitors, for combination therapy in AML. We demonstrate that selective HDAC1/2 inhibitors are highly effective and efficacious both as single agents and in combination with azacitidine in preclinical models of AML, including established AML cell lines, bone marrow samples freshly derived from AML patients and in vivo xenograft models of human AML. At the molecular level, gene expression profiling, DNA methylation mapping and chromatin immunoprecipitation analysis were performed on AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the drug combination. Molecular signatures and genes involved in myeloid cell differentiation, apoptosis and cell cycle arrest were identified as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients. Citation Format: Chengyin Min, Steven N. Quayle, Pengyu Huang, Jeffrey R. Shearstone, Simon S. Jones, Min Yang. Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 synergize with DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4724.