Pharmacologic modulation of chromatin remodeling in leu*

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DESCRIPTION (provided by applicant): Abnormal posttranslational histone modifications (i.e., lysine residue deacetylation/methylation) appear to have a significant role in leukemogenesis by disrupting gene expression and thereby leading to abnormal patterns of cell growth, differentiation and apoptosis in hematopoietic cells. In contrast to structural abnormalities (i.e., chromosome deletions or gene mutations) that cause irreversible loss of gene function, genomic silencing induced by these mechanisms can be relieved by pharmacologic modulation with histone deacetylase (HDAC) inhibitors. Recently, we have conducted preclinical studies demonstrating the activity of these agents with respect to gene re-expression, hematopoietic differentiation and apoptosis in myeloid and lymphoid leukemia cells. These studies have led to the translation of this therapeutic strategy from our laboratories into clinical trials for acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) (i.e., OSU 0051 and OSU 0336). Although we demonstrated in vivo biological and clinical activity of depsipeptide (FR228), a potent HDAC inhibitor, in both AML and CLL patients treated with weekly drug administration on OSU 0051 followed by one week of rest, regrowth between treatments and side effects such as chronic fatigue, anorexia and nausea prevented further development of this schedule. As the therapeutic potentials of depsipeptide in leukemia are remarkable and have not been fully explored yet, here, we propose to use a more dose-intensive, abbreviated schedule with treatments administered on days 1, 3, 5 of 21-day cycles. In the current proposal, we seek to: 1) define the feasibility of administering depsipeptide in AML and CLL using this new schedule; 2) assess the pharmacokinetics (PK) of depsipeptide and correlate them with pharmacodynamic (PD) and clinical results; 3) measure PD endpoints relevant to the biological activity of depsipeptide (i.e., inhibition of HDAC enzymatic activity, induction of histone posttranslational modifications, gene re-expression, cell surface antigen modulation and activation of common pathways of apoptosis). The potential mechanisms that mediate resistance to depsipeptide by overexpression of MDR1 and bcl-2 family members will also be investigated. The ultimate goal of our study is to recommend a tolerable and biologically active dose of depsipeptide for subsequent Phase II studies in AML and CLL. Further, we believe that this schedule is amenable to future combination-based approaches.