Current therapy can result in complete remission (CR) in nearly 90% of pediatric acute myeloid leukemia (AML) patients. Unfortunately, relapse AML (rAML) occurs in almost 50% of patients within two years of CR. Among them, more than 60% succumbed to AML within two years of relapse. Novel approaches are therefore needed to address the unmet medical needs of rAML. Recent studies suggest that leukemia stem cells (LSC) are highly resistant to conventional chemotherapy and thus are likely responsible for relapse. Therefore, therapeutic elimination of LSC may offer new approaches for the treatment of rAML. We have recently reported that hypoxia-inducible factor (HIF) 1a is activated in, and essential for, maintenance of AML stem cells. More importantly, at doses that have no recorded toxicity, Echinomycin, an HIF inhibitor, is effective in eliminating AML stem cells in xenogeneic mouse models and provides effective therapy for mouse rAML caused by mutations frequently found in pediatric AML. Echinomycin has been used in multiple phase I and phase II clinical trials in adult patients with solid tumors, although the drug has not been tested in hematological malignancies. Moreover, due to lack of analytic methods, these trials were performed without pharmacokinetic (PK) information. Nevertheless, these clinical trials demonstrated that Echinomycin is tolerated at doses that are 30- to 50-fold higher than our projected therapeutic doses based on data from xenogenic rAML models. Based on these exciting results, we propose herein a collaborative project involving investigators at Children's National Medical Center and the National Cancer Institute to carry out phase I clinical trials for children with relapsed AML. We will test the PK in non-human primates and fine-tune starting dose for human trials. We will also conduct dose escalation studies to identify a tolerable dose that results in significant reduction of rAML stem cells. We will develop and standardize a plasma inhibition assay for drug dosing in the future phase II and phase III clinical trials. Finally, to understand he mechanism of drug action, we will use chromatin- immunoprecipitation followed by next generation sequencing to identify HIF targets associated with the reduction of rAML stem cell activity. Our proposed studies will provide the much needed first-in-human data on PK/PD of Echinomycin, and provide a foundation for future phase II and phase III clinical trials aimed at the therapeutic elimination of cancer stem cells for pediatric AML.

Public Health Relevance

Relapse is the primary cause of the fatality associated with pediatric acute myeloid leukemia. The proposed studies take a new approach to attack the root cause of leukemia relapse, namely the leukemia stem cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA183030-02
Application #
8804250
Study Section
Special Emphasis Panel (ZCA1-SRLB-R (O1))
Program Officer
Merritt, William D
Project Start
2014-02-11
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
$628,352
Indirect Cost
$262,138
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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