DNA hypomethylating agents (HMA) promise to significantly advance the treatment of acute myelogenous leukemia (AML). The drugs are well tolerated in older patients who represent both the majority of adult AML, and those least well served by traditional, intensive chemotherapy. The dose and delivery schedule of HMAs strongly dictate biological activity but the pharmacodynamics of these agents is poorly understood. The absence of good biomarkers of DNA methylation is slowing the development of epigenetic therapy in AML. The long-term goal of this research is to develop effective and well-tolerated AML therapies that incorporate optimally dosed epigenetic modifiers. The objective of this application is to identify DNA methylation biomarkers that can be used to assess the activity of HMAs in AML leukemia stem/progenitor cells (LSPCs). The central hypothesis is that pharmacodynamic biomarkers of HMA activity have greatest clinical/biological relevance when they report efficacy within AML LSPCs. The rationale for the proposed studies is that, once AML-specific DNA methylation abnormalities are discovered, they can be used to assess the pharmacodynamic activity of HMAs in clinical trials designed to optimize the dose and delivery schedule of these agents for the treatment of AML. The hypothesis will be tested by pursuing two specific aims:
Aim 1 : Identify DNA methylation biomarkers of AML.
Aim 2 : Determine whether peripheral blood cells can be used as a surrogate tissue to assess decitabine-induced DNA hypomethylation in AML LSPCs. Under the first aim, a proven method for genome-wide analyses of DNA methylation that has already been established to be feasible in the applicants'hands, will be used to identify AML-specific abnormalities in CD34-selected primary, human AML LSPCs when compared to normal hematopoietic cells obtained from healthy donors.
The second aim will use previously collected, matched blood and bone marrow specimens obtained from patients with AML prior to and immediately following, several different decitabine administration schedules to identify AML-specific DNA methylation biomarkers suitable for pharmacodynamic monitoring in peripheral blood cells. These results are expected to have a positive impact on the clinical development of current and future DNA hypomethylating agents by providing a long sought after means to assess the biological activity of these agents in vivo. This contribution is significant be- cause it is a necessary first step in a continuum of research that is expected to yield pharmacodynamically tailored dosing of epigenetic modifiers that maximize anti-leukemic activity while minimizing toxicity. The pro- posed research is innovative because it represents a substantial departure from the current standard of measuring DNA methylation at a few convenient genomic loci in mixed cell populations long-after the delivery of a DNA HMA. Ultimately, the proposed genome-wide identification of AML-specific DNA methylation biomarkers in LSPCs and validation of celular surrogates with which to assess pharmacodynamics should permit rapid optimization, and perhaps personalization, of HMA schedules for the treatment of AML.
The proposed research is relevant to public health because the identification of AML-specific DNA methylation biomarkers for pharmacodynamics is ultimately expected to lead to optimized dosing regimens for DNA hypomethylating agents with reduced toxicity and maximal anti-leukemic activity. This work is consistent with the NIH goal of improving health, with the NCI mission of supporting research to advance the treatment of cancer and is responsive to the FOA in considering of the full array of potentially informative characteristics to trans-late basic science to a clinical application by providing a strong rationae for proposing DNA methylation bio- markers to address a current impediment to the rapid and rational development of hypomethylating agents for the treatment of AML.
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