Evaluation of entinostat alone and in combination with standard-of-care cytotoxic agents against rhabdomyosarcoma xenograft models

Raushan T. Kurmasheva, Abhik Bandyopadhyay, Edward Favours, Vanessa Del Pozo, Samson Ghilu, Doris A. Phelps, Stephen W. Erickson, Cody J. Peer, William D. Figg, Malcolm A. Smith, Peter J. Houghton

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3 Scopus citations

Abstract

Background: Entinostat, a selective class I histone deacetylase inhibitor, has been reported to enhance the activity of cytotoxic agents and suppress expression of PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). Procedures: Entinostat was tested against three rhabdomyosarcoma cell lines using 96-hour drug exposure. Entinostat alone or in binary combination with vincristine, actinomycin D or cyclophosphamide was tested in ARMS and two embryonal rhabdomyosarcoma (ERMS) xenograft models. Tumor growth was measured at weekly intervals. Drug-induced changes in acetylated histone H3(K9) and entinostat pharmacokinetics were determined. Results: In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 μM) with Tmax at 15 minutes, and total exposure (AUC0-12 h) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. Conclusions: Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.

Original languageEnglish (US)
Article numbere27820
JournalPediatric Blood and Cancer
Volume66
Issue number8
DOIs
StatePublished - Aug 2019

Keywords

  • chemotherapy
  • pediatric oncology
  • pharmacokinetics
  • pharmacology
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Kurmasheva, R. T., Bandyopadhyay, A., Favours, E., Del Pozo, V., Ghilu, S., Phelps, D. A., Erickson, S. W., Peer, C. J., Figg, W. D., Smith, M. A., & Houghton, P. J. (2019). Evaluation of entinostat alone and in combination with standard-of-care cytotoxic agents against rhabdomyosarcoma xenograft models. Pediatric Blood and Cancer, 66(8), [e27820]. https://doi.org/10.1002/pbc.27820