The role that epigenetic changes (i.e., histone deacetylation and DNA methylation) play in the aberrant silencing of tumor suppressor genes in malignant cells has been well established. There is now general consensus that both aberrant histone deacetylation and DNA methylation contribute to leukemogenesis in AML. Recent studies focused on the molecular basis of epigenetic transcriptional silencing support the concept that nuclear histones interact with DNA methylation in a dynamic way to repress genes important for hematopoietic differentiation and apoptosis. Genomic silencing induced by these mechanisms can be relieved by pharmacological modulation with histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. Preclinical work in AML has demonstrated in vitro synergy of these agents that raises the hope of clinical synergy. However, little is known about the specificity of this strategy for inhibiting specific HDAC and DNMT enzyme subtypes or the kinetics of enzyme inhibition and how this relates to clinic benefit in AML patients. Therefore, to understand their full potential, a systematic study of the pharmacological and biological effects induced by HDAC and DNMT inhibitors in the context of clinical trials is required. Here we propose to explore combination of agents with a demonstrated inhibitory activity to the histone deacetylation and DNA methylation machinery in AML. We hypothesize that the therapeutic application of these agents will restore normal patterns of gene expression, activate terminal differentiation and lower the apoptotic threshold in the leukemic cells, and thereby induce clinical benefit. To test these hypotheses, our specific aims are 1) to perform a phase I study in AML using agents that affect the DNA methylation machinery (i.e., decitabine) and chromatin structure (i.e., valproic acid); 2) to perform pharmacokinetic and pharmacodynamic studies of these agents that will allow correlations of drug plasma levels, chromatin changes and gene re-expression with toxicity and disease response. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102031-02
Application #
6872881
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$303,674
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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