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Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis

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Abstract

Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES.

Key messages

• Entinostat potently inhibits ES both in vitro and in vivo.

• EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment.

• Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling.

• HDAC3 is a transcriptional target of EWS-FLI1.

• HDAC3 is essential for ES cell viability and genomic stability maintenance.

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Acknowledgments

The authors gratefully acknowledge Dr. Jeff Hirst for technical help in flow cytometry assays and animal studies, Ms. Tara Meyer for technical assistance with H&E and immunohistochemical staining, Dr. Rashna Madan for reviewing the pathology slides, Dr. Richard C. Hastings for technical help in flow cytometry assays and data analysis, and Mr. Mitch Braun and Ms. Carolyn Vivian for assistance with animal studies. We also acknowledge the support of the University of Kansas Cancer Center’s Biospecimen Repository Core Facility and Lead Development and Optimization Shared Resource (P30 CA168524) and the University of Kansas Medical Center’s Flow Cytometry Core Laboratory (P30 GM103326).

Funding

This work was supported by an MCA Partners Advisory Board grant from Children’s Mercy Hospital and The University of Kansas Cancer Center (to KMC and AKG), Braden’s Hope for Childhood Cancer Foundation (to GS & AKG), and the Kansas Bioscience Authority Eminent Scholar Program (to AKG). AKG is the Chancellors Distinguished Chair in Biomedical Sciences Endowed Professor.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 4005B Wahl Hall East, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Yan Ma, Jennifer Crow & Andrew K. Godwin

  2. Lead Development Optimization Shared Resource, University of Kansas Cancer Center, Biotechnology Innovation and Optimization Center, Lawrence, KS, USA

    Michael Baltezor & Lian Rajewski

  3. Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA

    Michael Baltezor & Scott J. Weir

  4. Division of Hematology/Oncology, Children’s Mercy Kansas City, Kansas City, MO, USA

    Glenson Samuel & Katherine M. Chastain

  5. Health Services & Outcomes Research, Children’s Mercy Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA

    Vincent S. Staggs

  6. Department of Oncology, Georgetown University Medical Center, Washington, D.C., USA

    Jeffrey A. Toretsky

  7. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA

    Scott J. Weir

  8. University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA

    Scott J. Weir & Andrew K. Godwin

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  1. Yan Ma
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  2. Michael Baltezor
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  8. Jeffrey A. Toretsky
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Contributions

Y.M. and A.K.G. conceived and designed the study. Y.M., M.B., J.C., and V.S. developed the methodology. Y.M., M.B., L.R., J.C., and G.S. carried out experiments and collected data. Y.M., M.B., L.R., J.C., G.S., and V.S. analyzed, computed, and interpreted the data. Y.M. and M.B. wrote the manuscript. Y.M., M.B., L.R., J.C., G.S., V.S., K.M.C., J.A.T., S.J.W., and A.K.G. reviewed and revised the manuscript. M.B., S.J.W., and A.K.G. provided administrative, technical, and material support. A.K.G. supervised the study.

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Correspondence to Andrew K. Godwin.

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Ma, Y., Baltezor, M., Rajewski, L. et al. Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis. J Mol Med 97, 957–972 (2019). https://doi.org/10.1007/s00109-019-01782-0

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