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.
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.
|Li, Dongling; Hu, Minling; Liu, Ying et al. (2018) CD24-p53 axis suppresses diethylnitrosamine-induced hepatocellular carcinogenesis by sustaining intrahepatic macrophages. Cell Discov 4:6|
|Tang, Fei; Zhang, Peng; Ye, Peiying et al. (2017) A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice. Elife 6:|
|Liu, Yan; Wang, Yin; Du, Zhanwen et al. (2016) Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5. Cell Rep 15:1111-1122|
|Liu, Yang (2016) Neoantigen: A Long March toward Cancer Immunotherapy. Clin Cancer Res 22:2602-4|
|Peng, Gong; Liu, Yang (2015) Hypoxia-inducible factors in cancer stem cells and inflammation. Trends Pharmacol Sci 36:374-83|
|Wang, Yin; Liu, Yan; Tang, Fei et al. (2014) Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells. Blood 124:1127-35|