Stathis Anastasios, Zucca Emanuele, Bekradda Mohamed, Gomez-Roca Carlos, Delord Jean-Pierre, de La Motte Rouge Thibault, Uro-Coste Emmanuelle, de Braud Filippo, Pelosi Giuseppe, French Christopher A
Clinical Research Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Oncology Therapeutic Development, Clichy, France.
Cancer Discov. 2016 May;6(5):492-500. doi: 10.1158/2159-8290.CD-15-1335. Epub 2016 Mar 14.
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.
最初在NUT中线癌（NMC）中发现了含溴结构域和额外末端（BET）溴结构域（BRD）抑制剂的抗肿瘤、促分化作用，NMC是一种由BRD4-NUT融合癌蛋白驱动的侵袭性鳞状癌亚型。BRD4-NUT通过一种有效的染色质修饰机制阻断分化并维持肿瘤生长。OTX015/MK-8628是一种新型口服BET抑制剂，靶向BRD2/3/4/T，在NMC和其他几种肿瘤类型中具有临床前活性，目前正处于临床开发阶段。在4例确诊为BRD4-NUT融合的晚期NMC患者中评估了其抗肿瘤活性，这些患者在同情用药的情况下接受每日一次80mg OTX015/MK-8628治疗。2例患者迅速出现肿瘤消退和症状缓解，第3例患者病情有意义地稳定，伴有轻微代谢反应。主要副作用为轻度至中度胃肠道毒性和疲劳，以及可逆的3级血小板减少症。这是BRD抑制剂靶向BRD4-NUT具有临床活性的首个概念验证证据。
我们提供了首个临床概念验证，即使用BET抑制剂靶向BRD4-NUT可在NMC中产生显著且快速的抗肿瘤活性。它在这一罕见患者群体中作为单一药物或与其他药物联合使用具有很强的未来临床应用潜力。《癌症发现》；6(5)；492-500。©2016美国癌症研究协会。本文在本期特刊第461页被重点介绍。
