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

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

doi:10.18632/oncotarget.10983

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.

Highlights

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in Western countries and, despite improvements obtained with chemoimmunotherapy, up to half of these patients cannot be cured [1, 2]
Based on the in vitro synergism observed for combinations of OTX015 with other compounds [14], we evaluated the activity of combinations of this bromodomain inhibitor in an in vivo model of activated B-cell like (ABC)-DLBCL
Mice bearing xenografts of the ABCDLBCL cell line SU-DHL-2 were treated with control or OTX015, Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, the mechanistic target of rapamycin inhibitor everolimus, the histone deacetylase inhibitor vorinostat, or the antiCD20 monoclonal antibody rituximab as single agents or in OTX015-containing combinations

Summary

INTRODUCTION

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in Western countries and, despite improvements obtained with chemoimmunotherapy, up to half of these patients cannot be cured [1, 2]. BET proteins are key epigenetic regulators of gene transcription and their inhibition has resulted in antitumor activity in different tumor models, including lymphomas [11,12,13,14,15,16,17,18,19,20]. OTX015 has in vitro and in vivo antitumor activity as a single agent in different lymphoma models, including ABC-DLBCL [14]. The mechanism of action of BET inhibitors is likely pleiotropic, down-regulation of genes involved in B cell identity and germinal center formation, and, especially in the ABC-DLBCL setting in which such effects can lead to apoptosis, inhibition of the B-cell receptor and nuclear factor kB signaling pathways play an important role [12,13,14]. Since OTX015 presented in vitro synergism when combined with different agents in lymphoma models [14], we evaluated the in vivo activity of OTX015-containing combinations in an ABC-DLCBL xenograft model

RESULTS AND DISCUSSION

MATERIALS AND METHODS

CONFLICTS OF INTEREST