Treatment options for adult patients with leukemia remain sub-optimal, and therefore new rationally designed therapies are needed. Two epigenetic alterations are currently the focus of intense investigation: DNA methylation of promoter CpG islands, and changes in the histone code associated with distinct levels of chromatin compaction and gene expression. These are of interest because: 1) they are observed at high frequency in patients with leukemia; 2) both have a role in gene expression and are intimately associated; and 3) can be modulated using hypomethylating agents and histone deacetylase inhibitors (HDACI) with preclinical and clinical activity. Results of a phase I study of low-dose 5-aza-2'-deoxycytidine (decitabine), a hypomethylating agent, performed at our institution, have shown that decitabine has significant activity at doses of 15 mg/m2 daily X 10 days. Valproic acid is an oral anti-convulsant agent with potent HDACI activity at physiological doses, also with an excellent safety profile. Based on this, we propose the hypothesis that the combination of decitabine and valproic acid will be well tolerated and will have significant antileukemia activity. To test this hypothesis, we propose the following aim: to conduct a phase I/II study of low-dose decitabine with escalating doses of valproic acid. The study will be monitored for toxicity, clinical response, and changes in histone acetylation, DNA methylation and gene expression. This study will have important implications, as it will provide fundamental knowledge regarding the clinical and molecular implications in vivo of the combination of a DNA hypomethylating agent and a HDACI. Decitabine will be generously provided by SuperGen (r). Valproic acid is an FDA approved anti-convulsant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA105771-02
Application #
6934546
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
2004-08-09
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$309,550
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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