title: Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.
abstract: The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4-NUT.
  
  
  
  We present the first clinical proof-of-concept that targeting BRD4-NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492-500. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
authors.affiliation: Clinical Research Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. anastasios.stathis@eoc.ch cfrench@partners.org.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stathis
authors.affiliation: Clinical Research Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Zucca
authors.affiliation: Oncology Therapeutic Development, Clichy, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bekradda
authors.affiliation: Clinical Research Unit, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gomez-Roca
authors.affiliation: Clinical Research Unit, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.affiliation: Institut Curie, Hôpital René Huguenin, Saint Cloud, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: de La Motte Rouge
authors.affiliation: Department of Pathology, Toulouse University Hospital and INSERM U1037, IUCT-Oncopole, Toulouse, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, Department of Oncology, Università degli Studi di Milano, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori and Department of Biological and Clinical Sciences "Luigi Sacco," Università degli Studi, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. anastasios.stathis@eoc.ch cfrench@partners.org.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
mesh_terms: D000083:Acetanilides / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001706:Biopsy; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D017809:Fatal Outcome; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000072078:Positron Emission Tomography Computed Tomography; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; C471990:BRD4-NUT fusion oncogene protein, human; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; D009687:Nuclear Proteins; C000605331:OTX015; D015514:Oncogene Proteins, Fusion