Oncotarget

Research Papers:

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

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Oncotarget. 2016; 7:58142-58147. https://doi.org/10.18632/oncotarget.10983

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Abstract

Eugenio Gaudio1, Chiara Tarantelli1, Maurilio Ponzoni2, Elodie Odore3, Keyvan Rezai3, Elena Bernasconi1, Luciano Cascione1,4, Andrea Rinaldi1, Anastasios Stathis4, Eugenia Riveiro5, Esteban Cvitkovic5, Emanuele Zucca4, Francesco Bertoni1,4

1Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland

2San Raffaele Scientific Institute, Milan, Italy

3Institut Curie, Hôpital René Huguenin, Saint-Cloud, France

4Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

5Oncology Therapeutic Development, Clichy, France

Correspondence to:

Francesco Bertoni, email: frbertoni@mac.com

Keywords: BET inhibitor, ibrutinib, rituximab, vorinostat, everolimus

Received: April 28, 2016     Accepted: July 07, 2016     Published: August 1, 2016

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.


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