title: The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs.
abstract: OBJECTIVE
  In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.
  
  
  METHODS
  We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.
  
  
  RESULTS
  OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.
  
  
  CONCLUSIONS
  Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Michela
authors.initials: M
authors.lastname: Boi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Bonetti
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tarantelli
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Monica
authors.initials: M
authors.lastname: Testoni
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Afua Adjeiwaa
authors.initials: AA
authors.lastname: Mensah
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stathis
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Stussi
authors.affiliation: OTD Oncology Therapeutic Development, Clichy, France.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Riveiro
authors.affiliation: Oncoethix, Lausanne, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Herait
authors.affiliation: Department of Pathology and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York. Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, New York.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: OTD Oncology Therapeutic Development, Clichy, France. Oncoethix, Lausanne, Switzerland.
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. frbertoni@mac.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D009687:Nuclear Proteins; C000605331:OTX015