title: Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma.
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.
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors: Eugenio
authors: E
authors: Gaudio
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors: Chiara
authors: C
authors: Tarantelli
authors: San Raffaele Scientific Institute, Milan, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Institut Curie, Hôpital René Huguenin, Saint-Cloud, France.
authors: Elodie
authors: E
authors: Odore
authors: Institut Curie, Hôpital René Huguenin, Saint-Cloud, France.
authors: Keyvan
authors: K
authors: Rezai
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors: Elena
authors: E
authors: Bernasconi
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.|Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors: Luciano
authors: L
authors: Cascione
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors: Andrea
authors: A
authors: Rinaldi
authors: Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors: Anastasios
authors: A
authors: Stathis
authors: Oncology Therapeutic Development, Clichy, France.
authors: Eugenia
authors: E
authors: Riveiro
authors: Oncology Therapeutic Development, Clichy, France.
authors: Esteban
authors: E
authors: Cvitkovic
authors: Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors: Emanuele
authors: E
authors: Zucca
authors: Lymphoma and Genomics Research Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.|Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors: Francesco
authors: F
authors: Bertoni
mesh_terms: D000083:Acetanilides / Q000494:pharmacology* / Q000627:therapeutic use; D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D000069283:Rituximab / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000605331:OTX015; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000077337:Vorinostat; D000068338:Everolimus; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D058570:TOR Serine-Threonine Kinases; D000225:Adenine
keywords: BET inhibitor; everolimus; ibrutinib; rituximab; vorinostat