Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma

Eugenio Gaudio, Chiara Tarantelli, Maurilio Ponzoni, Elodie Odore, Keyvan Rezai, Elena Bernasconi, Luciano Cascione, Andrea Rinaldi, Anastasios Stathis, Eugenia Riveiro, Esteban Cvitkovic, Emanuele Zucca, Francesco Bertoni

Research output: Contribution to journalArticle

Abstract

The bromodomain inhibitor OTX015 (MK-8628) has shown anti-lymphoma activity as a single agent in both the preclinical and clinical settings, as well as in vitro synergism with several anticancer agents. Here, we report in vivo data for OTX015 in combination with the histone deacetylase inhibitor vorinostat, the Bruton's tyrosine kinase inhibitor ibrutinib, the anti-CD20 monoclonal antibody rituximab, and the mTOR inhibitor everolimus in a diffuse large B cell lymphoma model. The antitumor effect of OTX015-containing combinations in SU-DHL-2 xenografts in mice was much stronger than the activity of the corresponding single agents with almost complete tumor eradication for all four combinations. Pharmacokinetic analyses showed similar OTX015 levels in plasma and tumor samples of approximately 1.5 μM, which is equivalent to the concentration showing strong in vitro activity. For all four combinations, mean terminal levels of the bromodomain inhibitor differed from those in mice exposed to single agent OTX015, indicating a need for thorough pharmacokinetic investigations in phase I combination studies. In conclusion, our results provide a strong rationale to explore OTX015-containing combinations in the clinical lymphoma setting.

Original languageEnglish
Pages (from-to)58142-58147
Number of pages6
JournalOncotarget
Volume7
Issue number36
DOIs
Publication statusPublished - 2016

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Keywords

  • BET inhibitor
  • Everolimus
  • Ibrutinib
  • Rituximab
  • Vorinostat

ASJC Scopus subject areas

  • Oncology

Cite this

Gaudio, E., Tarantelli, C., Ponzoni, M., Odore, E., Rezai, K., Bernasconi, E., Cascione, L., Rinaldi, A., Stathis, A., Riveiro, E., Cvitkovic, E., Zucca, E., & Bertoni, F. (2016). Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. Oncotarget, 7(36), 58142-58147. https://doi.org/10.18632/oncotarget.10983