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Oncotarget. 2016 Sep 6;7(36):58142-58147. doi: 10.18632/oncotarget.10983.

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

Author information

1
Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
2
San Raffaele Scientific Institute, Milan, Italy.
3
Institut Curie, Hôpital René Huguenin, Saint-Cloud, France.
4
Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
5
Oncology Therapeutic Development, Clichy, France.

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.

KEYWORDS:

BET inhibitor; everolimus; ibrutinib; rituximab; vorinostat

PMID:
27494885
PMCID:
PMC5295419
DOI:
10.18632/oncotarget.10983
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

FB, KR, AS and EZ have received institutional research funds from Oncology Therapeutic Development. Esteban Cvitkovic was founder and CSO of Oncoethix SA, and CEO of Oncology Therapeutic Development. Maria E. Riveiro was an employee of Oncology Therapeutic Development. EZ has received research funds from Celgene, Novartis, Mundipharma, Roche, Pharmacyclics Inc., Johnson & Johnson's Janssen Pharmaceutical, Gilead. The remaining authors have no conflicts of interest.

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