DEPSIPEPTIDE: A NOVEL HISTONE DEACYTLASE INHIBITOR IN L

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): A fine balance between the enzymatic activity of histone acetyltransferase and histone deacetylase (HDAC) governs levels of posttranslation acetylation of histone lysine residues. Recognition of this regulatory mechanism for gene transcriptional activation is growing. In cell transformation, acetylation is profoundly altered, and accumulation of hypoacetylated histone species occurs. Depsipeptide is a novel HDAC inhibitor completing phase I development in solid tumors; clinical activity has been noted. Studies by our group have shown selective cytotoxicity of depsipeptide toward acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells compared to normal hematopoetic cells. This cytotoxic effect occurs via an uncommonly exploited pathway of apoptosis, and the effect appears to be related to increasing histone H3 and H4 acetylation. We have demonstrated the ability of depsipeptide to induce gene transcription, cell differentiation, and expression of adhesion/co-stimulatory molecules in human myeloid cell lines and transformed lymphocytes. Synergy with decitabine and up-regulation of the 1D10 antigen was also noted. Based upon these data, we propose to perform the first clinical trial of depsipeptide in leukemia patients in two separate cohorts (AML and CLL). The objectives of our proposal are to 1) determine the safety of administering depsipeptide to two cohorts of leukemia patients (AML and CLL) 2) determine the dose at which a 100 percent increase in the baseline histone acetylation occurs, which will define a minimal effective pharmacologic dose (MEPD) 3) examine the biologic effect of depsipeptide on leukemia cells treated in vivo in patients with CLL and AML with respect to differentiation (AML) and co-stimulatory/adhesion molecule expression(AML and CLL). The specific relationship of these processes to lysine-specific H4 alterations, inhibition of HDAC enzyme activity, and enhanced ex vivo sensitivity to monoclonal antibodies will be assessed. By utilizing this novel study design that target MEPD, we may achieve significant biological effects, while avoiding excess doses of depsipeptide. The clinical and laboratory results of this trial will provide pharmacokinetic and pharmacodynamic information for additional correlative efforts in both single agent phase II and combination phase I studies.