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

被引：22

作者：

Gaudio, Eugenio ^{[1
]}

Tarantelli, Chiara ^{[1
]}

Ponzoni, Maurilio ^{[2
]}

Odore, Elodie ^{[3
]}

Rezai, Keyvan ^{[3
]}

Bernasconi, Elena ^{[1
]}

Cascione, Luciano ^{[1
,4
]}

Rinaldi, Andrea ^{[1
]}

Stathis, Anastasios ^{[4
]}

Riveiro, Eugenia ^{[5
]}

Cvitkovic, Esteban ^{[5
]}

Zucca, Emanuele ^{[4
]}

Bertoni, Francesco ^{[1
,4
]}

机构：

[1] Inst Oncol Res IOR, Lymphoma & Genom Res Program, Bellinzona, Switzerland

[2] Ist Sci San Raffaele, Milan, Italy

[3] Hop Rene Huguenin, Inst Curie, St Cloud, France

[4] Oncol Inst Southern Switzerland IOSI, Bellinzona, Switzerland

[5] Oncol Therapeut Dev, Clichy, France

来源：

ONCOTARGET | 2016年 / 7卷 / 36期

关键词：

BET inhibitor; ibrutinib; rituximab; vorinostat; everolimus; B-CELL LYMPHOMA; SUPER-ENHANCERS; DOSE-ESCALATION; ACUTE-LEUKEMIA; TRANSCRIPTION; NEOPLASMS; IBRUTINIB; IDENTITY; PHASE-1; MODELS;

D O I：

10.18632/oncotarget.10983

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 mu M, 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.

引用

页码：58142 / 58147

页数：6

共 31 条

[31] AS703569/R763, a pan Aurora kinase inhibitor, shows strong antitumor activity in vitro and in vivo in a panel of triple-negative breast cancer cell lines and xenografts
Marangoni, E.
Clark, A.
Assayag, F.
Chateau-Joubert, S.
Hamini, A.
Poupon, M. F.
Liu, E.
Spooner, A.
Romanelli, A.
Decaudin, D.
EJC SUPPLEMENTS, 2010, 8 (07): : 157 - 158

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