Research Papers:

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

Joanna Zabkiewicz _, Marie Gilmour, Robert Hills, Pares Vyas, Elizabeth Bone, Alan Davidson, Alan Burnett and Steven Knapper

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Oncotarget. 2016; 7:16650-16662. https://doi.org/10.18632/oncotarget.7692

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Joanna Zabkiewicz1, Marie Gilmour1, Robert Hills1, Pares Vyas2, Elizabeth Bone3, Alan Davidson3, Alan Burnett1, Steven Knapper1

1Department of Haematology, Experimental Cancer Medicine Centre (ECMC), Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK

2Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

3Chroma Therapeutics, Abingdon, UK

Correspondence to:

Joanna Zabkiewicz, e-mail: ZabkiewiczJ1@cardiff.ac.uk

Keywords: AML, HDACi, CMML, tefinostat, hCE-1

Received: August 14, 2015     Accepted: January 17, 2016     Published: February 25, 2016


Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs.

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