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Therapeutic targeting of TP53-mutated acute myeloid leukemia by inhibiting HIF-1α with echinomycin

Oncogene volume 39, pages 3015–3027 (2020)Cite this article

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Abstract

TP53 mutation in acute myeloid leukemia (AML) is associated with poor prognosis. Since no targeted therapy is available to restore p53 function, it is of great interest to test whether other pathways activated by TP53 mutations can be therapeutically targeted. Here, we showed HIF-1α target genes are enriched in TP53-mutated versus TP53-wild-type AML. To determine the role of this activation, we tested efficacy of HIF-1α inhibitor echinomycin in TP53-mutated AML samples in vitro and in vivo. Echinomycin was broadly effective against a panel of primary AML blast cells, with low nanomolar IC50s and, based on colony-forming unit assay, was tenfold more effective in eliminating AML stem cells. Echinomycin selectively eliminated CD34+CD38− AML cells. To test the therapeutic efficacy of echinomycin, we established a xenograft model of TP53-mutated AML. Echinomycin was broadly effective against xenografts from multiple AML samples in vivo, and more effective than cytarabine + daunorubicin chemotherapy. Importantly, while cytarabine + daunorubicin enriched for AML stem cells, echinomycin nearly eliminated this population. Using TP53-mutated AML cell line THP1 and patient-derived AML cells, we tested a new echinomycin formulation with longer half-life and significantly improved therapeutic effect. Our data suggest a novel approach to treat AML with TP53 mutations.

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Fig. 1: Echinomycin significantly inhibits expansion of human TP53-mutant AML cells in vitro.
Fig. 2: Echinomycin significantly suppresses expansion of human TP53-mutated AML cells in a mouse xenograft model.
Fig. 3: Echinomycin has therapeutic efficacy in most human TP53-mutated AMLs.
Fig. 4: Liposomal echinomycin suppressed the growth of human TP53 null THP1 cells and patient-derived xenograft TP53-mutated AML 12 cells in xenograft mouse model.
Fig. 5: Liposomal echinomycin suppressed the growth of human patient-derived xenograft TP53-mutated AML cells in xenograft mouse model.

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Acknowledgements

This study was supported by grants from the National Institutes of Health National Cancer Institute [CA171972, CA183030 (YL) and CA164469 (YW)] and a grant from OncoImmune, Inc. Some of the studies were performed when the authors were at the Children’s National Medical Center in Washington, DC.

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Authors and Affiliations

  1. Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Yin Wang, Yan Liu, Christopher Bailey, Peng Zhang, Pan Zheng & Yang Liu

  2. Graduate Program of Integrated Biomedical Research, George Washington University School of Medicine, Washington, DC, 20052, USA

    Christopher Bailey

  3. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA

    Huixia Zhang, Miao He & Duxin Sun

  4. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Brian Parkin & Sami N. Malek

  5. Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA

    Maria R. Baer

  6. OncoImmune, Inc., Rockville, MD, 20853, USA

    Pan Zheng & Yang Liu

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  1. Yin Wang
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Correspondence to Yin Wang or Yang Liu.

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YL and PZ are cofounders and employee of, and have equity interest in OncoImmune, Inc. All other authors declare no conflicts of interest.

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Wang, Y., Liu, Y., Bailey, C. et al. Therapeutic targeting of TP53-mutated acute myeloid leukemia by inhibiting HIF-1α with echinomycin. Oncogene 39, 3015–3027 (2020). https://doi.org/10.1038/s41388-020-1201-z

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