Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma
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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
Francesco Bertoni, email: [email protected]
Keywords: BET inhibitor, ibrutinib, rituximab, vorinostat, everolimus
Received: April 28, 2016 Accepted: July 07, 2016 Published: August 1, 2016
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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