The majority of children and adults with acute myeloid leukemia (AML) die of their disease and therefore, novel therapeutic approaches beyond """"""""one-fits-all"""""""" chemotherapy regimens are required. Epigenetic gene silencing has been reported to be involved in the deregulation of hematopoietic cell proliferation, differentiation and survival in AML and contributes to leukemogenesis. We have been focusing on pharmacological targeting of aberrant DNA methylation that mediates epigenetic gene silencing in AML. Decitabine (DAC) is an azanucleoside with hypomethylating activity. In the last funding cycle of this R01 grant, we have brought to the clinic and demonstrated the excellent activity of a regimen of low-dose DAC (20 mg/m2/day x10 day) and the feasibility of the combination of DAC with the proteasome inhibitor bortezomib. We have shown that untreated older AML patients can achieve a complete remission rate of approximately 50% with these DAC-based regimens. In addition we have made several discoveries with regard to: (a) potential molecular predictors of clinical response to DAC (miR-29b and DNMT3A mutations);(b) novel mechanisms of myeloid leukemogenesis involving epigenetics, microRNAs and kinases, and (c) novel compounds that enhance the pharmacologic activity of DAC through up regulation of microRNAs (i.e., AR42, a histone deacetylase inhibitor designed and developed at the OSU). These novel clinical, molecular and pharmacologic findings now need to be validated and their mechanisms further understood in order to move forth the epigenetic-targeting approaches in AML. To achieve this goal, we also need to define the molecular basis for treatment resistance to epigenetic-targeting therapies, not only at the level of bulk AML blasts, but also in leukemia stem cells (LSC). Thus, we have now designed two new clinical trials and a series of novel pharmacodynamic studies that will unveil the interplay among DNA hypermethylation, microRNAs, and LSC through the following Specific Aims: (1)To conduct a larger Phase II clinical trial (CALGB 11002) in untreated older (>60 years) AML to compare the clinical activity of decitabine (DAC) vs. decitabine (DAC) + bortezomib and identify the predictive and pharmacodynamic (PD) factors that determine therapeutic differences between these two regimens;(2) To conduct a Phase I clinical trial (OSU 11130) of the HDAC inhibitor AR42 followed by DAC (AR42->DAC) to define toxicity, clinical response and pharmacokinetic (PK) and pharmacodynamic (PD) factors that determine the clinical outcomes in adult and pediatric patients with AML;(3) To determine the impact of epigenetic- targeting therapies on the function and survival of leukemic stem cells (LSCs) and how this contributes to disease response or resistance in AML patients to DAC-based regimens.
The majority of AML patients die of their disease when treated with conventional chemotherapy. This calls attention to the need for novel treatments. One of the processes contributing to AML is abnormal deregulation of gene functions through a mechanism called epigenetic silencing. Our overall goal is to target this abnormal mechanism with novel and non-toxic clinical approaches that include FDA approved agents already in the clinic (i.e., decitabine, bortezomib) and others that we have developed to potentiate the activity of the former (i.e., AR42). We propose here to test these new approaches through two new clinical trials and a series of laboratory studies comprising genetic and drug level analyses that will provide insights for the success or failure of the proposed new approaches.
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