Abstract B84: Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 significantly enhance the activity of the 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. There is a great need for novel approaches to treat AML due to limited improvements in the treatment of patients over the past several decades. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and the DNA methyltransferase inhibitor azacitidine is approved for the treatment of myelodysplastic (MDS), which frequently progresses to AML, and is commonly used in AML patients. 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. Selective HDAC inhibitors are predicted to reduce combination drug toxicity and other side effects observed with pan-HDAC inhibitors, while still enabling therapeutic benefits. In this work, we demonstrate that potent and selective inhibitors of HDAC1/2 are highly efficacious both as single agents and in combination with azacitidine in preclinical models of AML, including established AML cell lines and bone marrow samples freshly derived from AML patients. Combination treatment in vivo demonstrated good tolerability, and ongoing efficacy studies in AML xenograft models will be discussed. At the molecular level, gene expression profiling and DNA methylation mapping were performed on MV4-11 cells treated with an HDAC1/2 inhibitor, azacitidine, or the combination. Molecular signatures were analyzed by GSEA. Significantly more genes and signatures were upregulated than downregulated by the single agent and combination treatments, consistent with the transcription activation mechanism of these compounds. 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 and potentially MDS 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 significantly enhance the activity of the DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B84.