Abstract 5372: 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) (2015)

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 since the development of cytarabine and daunorubicin combination therapy. 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. Numerous clinical studies are ongoing to investigate the benefit of combining azacitidine with other investigational agents in AML. HDAC inhibitors are emerging as promising agents for the treatment of AML. Selective HDAC inhibitors are predicted to reduce the combination drug toxicity and other side effects observed with non-selective HDAC inhibitors, while also realizing beneficial therapeutic effects. One example is ricolinostat (ACY-1215), a first-in-class orally available HDAC inhibitor that is 11-fold selective for HDAC6, synergizes with proteasome inhibitors (Santo, et al, Blood, 2012) and immunomodulatory agents (Quayle, et al, ASH, 2013) in preclinical models of B-cell malignancies, which has thus far demonstrated an improved safety and tolerability profile in Phase I trials in multiple myeloma (Raje, Haematological, 2014, Suppl 1). In this work, we evaluated the efficacy of azacitidine in combination with selective inhibitors of either HDAC1/2, HDAC3 or HDAC6 on AML cells. Comparison of the panel of selective HDAC inhibitors demonstrated that HDAC1/2 inhibition is sufficient to reduce cell viability, induce differentiation, arrest cell cycle progression and initiate apoptosis in multiple AML cell lines. Selective inhibition of HDAC3 induced differentiation yet had no effect on cell cycle progression or apoptosis, while selective inhibition of HDAC6 had no effect on differentiation, cell cycle arrest or apoptosis in these cells. Furthermore, combining HDAC1/2 inhibition with azacitidine led to significantly enhanced induction of differentiation and apoptosis, and decreases in AML cell viability compared to either agent alone. Ongoing studies exploring the molecular mechanism underlying the activity of selective HDAC1/2 inhibitors, as well as the activity of combination treatment with azacitidine in primary AML cells and animal models of AML, will be discussed. Together, these findings provide support for 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, David Tamang, 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 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 5372. doi:10.1158/1538-7445.AM2015-5372