Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.
Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.
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DOI：
10.1158/2159-8290.cd-15-1335
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发表时间：
2016-05
期刊：
影响因子：
28.2
通讯作者：
French CA
中科院分区：
文献类型：
--
作者：
Stathis A;Zucca E;Bekradda M;Gomez-Roca C;Delord JP;de La Motte Rouge T;Uro-Coste E;de Braud F;Pelosi G;French CA
溴域和外端（BET）溴域（BRD）抑制剂的抗肿瘤、促分化作用最初是在NUT中线癌（NMC）中发现的，NMC是一种由BRD4-NUT融合癌蛋白驱动的侵袭性鳞状癌症亚型。BRD4-NUT通过有效的染色质修饰机制阻断肿瘤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，目前处于临床开发阶段。在4例确诊BRD4-NUT融合的晚期NMC患者中，研究人员评估了这些患者的抗肿瘤活性，这些患者在有同情心的使用环境下每天接受一次80 mg OTX015/MK-8628治疗。两名患者迅速出现肿瘤消退和症状缓解，第三名患者有意义的疾病稳定，伴有轻微的代谢反应。主要副作用为轻度至中度胃肠道毒性和疲劳，以及可逆性3级血小板减少症。这是首个针对BRD4-NUT的溴结构域抑制剂临床活性的概念验证证据。
The anti-neoplastic, pro-differentiative 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 advanced stage NMC patients 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 bromodomain inhibitor in targeting BRD4-NUT.