Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.
- Stathis A Clinical Research Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. anastasios.stathis@eoc.ch cfrench@partners.org.
- Zucca E Clinical Research Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Bekradda M Oncology Therapeutic Development, Clichy, France.
- Gomez-Roca C Clinical Research Unit, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
- Delord JP Clinical Research Unit, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
- de La Motte Rouge T Institut Curie, Hôpital René Huguenin, Saint Cloud, France.
- Uro-Coste E Department of Pathology, Toulouse University Hospital and INSERM U1037, IUCT-Oncopole, Toulouse, France.
- de Braud F Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, Department of Oncology, Università degli Studi di Milano, Milan, Italy.
- Pelosi G 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.
- French CA Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. anastasios.stathis@eoc.ch cfrench@partners.org.
- 2016-03-16
Published in:
- Cancer discovery. - 2016
Acetanilides
Adult
Aged
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Biopsy
Carcinoma
Cell Line, Tumor
Fatal Outcome
Female
Heterocyclic Compounds, 3-Ring
Humans
In Situ Hybridization, Fluorescence
Male
Molecular Targeted Therapy
Neoplasm Grading
Neoplasm Staging
Nuclear Proteins
Oncogene Proteins, Fusion
Positron Emission Tomography Computed Tomography
Treatment Outcome
Young Adult
English
UNLABELLED
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.
SIGNIFICANCE
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.
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.
SIGNIFICANCE
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/2159-8290.CD-15-1335
- PMID 26976114
- Persistent URL
- https://folia.unifr.ch/global/documents/58605
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