Pathogenesis and Treatment of NUT midline carcinoma

NUT中线癌的发病机制和治疗

• 批准号: 10655930
• 负责人: Christopher A French
• 金额: $ 42.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655930
• 关键词: Acetylation; Affect; Age; Binding; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CDKN2A gene; Carcinoma; Cell Cycle; Chromatin; Collaborations; Complex; Data; Disease; EP300 gene; EZH2 gene; Enhancers; Epigenetic Process; Exclusion; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Histone Acetylation; Histones; Human; In Vitro; Maintenance; Malignant Neoplasms; Methylation; Methyltransferase; Modeling; Mus; Oncogenes; Oncogenic; Oncoproteins; Outcome; Pathogenesis; Patients; Phase; Polycomb; Principal Investigator; Proliferating; Protein Family; Proteins; Repression; Role; Squamous cell carcinoma; Testing; Therapeutic; Toxic effect; Transcription Coactivator; Tumor Suppressor Genes; Xenograft procedure; derepression; effective therapy; gene repression; histone acetyltransferase; improved; in vivo; inhibitor therapy; novel; permissiveness; pre-clinical; programs; recruit; senescence; small molecule; synergism; therapeutic target; therapeutically effective; tumor

Project Summary Abstract. NUT carcinoma (NC, formerly NUT midline carcinoma) is an aggressive squamous carcinoma, affecting all ages, that is highly (>90%) lethal. The over-arching goal of this proposal is to improve survival of these patients through mechanism-driven identification of key oncogenic targets. NC is defined by NUTM1-fusion oncogenes, most commonly (~78%) encoding the BRD4-NUT protein. BRD4-NUT drives NC growth through the blockade of differentiation and maintenance of proliferation by forming very large (100kb-2MB), acetyl-histone-rich super-enhancers called megadomains (MD) that we described. MDs arise from the recruitment of p300, a histone acetyl-transferase (HAT), by NUT to acetylated histones bound by the dual bromodomains of BRD4, a BET family protein. We have shown that BRD4-NUT drives transcription of key oncogenic targets through the additional recruitment of numerous transcriptional activators by BRD4. Our demonstration that treatment with BET bromodomain inhibitors (BETi) that competitively inhibit binding of BET bromodomains to chromatin, can inhibit growth of NC in humans led to a new field investigating the role of BRD4 in cancer. Unfortunately, the efficacy of BETi monotherapy is limited by toxicity. In this next phase, we are investigating novel oncogenic mechanisms whose targeting can synergize with BETi therapeutically. Our preliminary data, together with what is established, has led us to formulate a mechanistic two-domain model of how NC growth is epigenetically driven. The model will be tested in the aims below with the overall goal of identifying a therapeutic combination of compounds optimized for maximally selective, synergistic tumor inhibition with minimized toxicity. The model proposes that the first, transcriptionally repressive domain formed by PRC2 enables NC growth by repressing the expression of pro-differentiation, tumor suppressive genes (tested in aim 1). The second, physically separate permissive MD is comprised of BRD4-NUT-p300 bound to acetylated histones that drive transcription of oncogenic genes. In this model, MD formation requires cooperative binding of both BRD4-NUT bromodomains (BD1 and BD2) to acetylated histones (tested in aim 2); and the acetyl- histone-permissive state that enables MD formation requires mono-methylation of H3K79 by DOT1L (aim 3). Inhibition of both of these domains would 1. repress transcription of oncogenic genes, such as MYC, and 2. de- repress transcription of genes critical for differentiation, senescence, and exit from cell cycle. Indeed, we have found that co-inhibition of EZH2 and BRD4-NUT is synergistic in vitro and in vivo. Specific Aim 1. Determine the oncogenic role of EZH2 in NUT carcinoma. Specific Aim 2. Determine the oncogenic roles of BRD4 bromodomains 1 and 2 in NUT carcinoma. Specific Aim 3. What is the role of DOT1L in BRD4-NUT megadomain formation and oncogenic function?

项目摘要摘要。NUT癌（NC，以前称为NUT中线癌）是一种侵袭性肿瘤， 鳞状细胞癌，影响所有年龄，是高度（>90%）致命。这项建议的首要目标是 通过机制驱动的关键致癌靶点鉴定来提高这些患者的生存率。NC是 由NUTM 1融合癌基因定义，最常见（约78%）编码BRD 4-NUT蛋白。BRD4-NUT 通过阻断分化和维持增殖来驱动NC生长， （100 kb-2 MB），我们描述的富含乙酰基组蛋白的超级增强子，称为巨蛋白（MD）。MD出现 从p300的募集，一种组蛋白乙酰转移酶（HAT），通过NUT到乙酰化的组蛋白结合， BRD 4的双溴结构域，BET家族蛋白。我们已经表明，BRD 4-NUT驱动转录的关键 BRD 4通过额外募集大量转录激活因子来调节肿瘤靶点。 我们证明，用竞争性抑制结合的BET布罗莫结构域抑制剂（BETi）治疗， BET溴结构域对染色质的作用，可以抑制NC在人类中的生长，导致了一个新的领域的研究作用， BRD 4在癌症中的作用不幸的是，BETi单一疗法的疗效受到毒性的限制。 在下一阶段，我们正在研究新的致癌机制，其靶向可以协同 Beti治疗。我们的初步数据，加上已经确定的，使我们制定了一个 NC生长如何由表观遗传学驱动的机械双域模型。该模型将在目标中进行测试 总体目标是鉴定优化的化合物的治疗组合， 选择性、协同性肿瘤抑制，毒性最小。该模型提出，第一，转录 PRC 2形成的抑制结构域通过抑制促分化的表达使NC生长， 肿瘤抑制基因（在目标1中测试）。 第二个物理上分离的允许性MD由结合至乙酰化的BRD 4-NUT-p300组成。 驱动致癌基因转录的组蛋白。在这个模型中，MD的形成需要协同结合 BRD 4-NUT溴结构域（BD 1和BD 2）与乙酰化组蛋白的结合（在目的2中测试）;以及乙酰基-NUT溴结构域（BD 1和BD 2）与乙酰化组蛋白的结合（在目的2中测试）。 能够形成MD的组蛋白允许状态需要H3 K79被DOT 1 L单甲基化（目的3）。 抑制这两个域将1。抑制致癌基因如MYC的转录，和2.去 抑制分化、衰老和退出细胞周期的关键基因的转录。我确已 发现EZH 2和BRD 4-NUT的共抑制在体外和体内是协同的。 具体目标1.确定EZH 2在NUT癌中的致癌作用。 具体目标2。确定BRD 4布罗莫结构域1和2在NUT癌中的致癌作用。 具体目标3。DOT 1 L在BRD 4-NUT巨链形成和致癌性中的作用是什么？ 功能？

项目成果

NUT Carcinoma of the Salivary Glands: Clinicopathologic and Molecular Analysis of 3 Cases and a Survey of NUT Expression in Salivary Gland Carcinomas.

• DOI: 10.1097/pas.0000000000001046
• 发表时间: 2018-07
• 期刊: The American journal of surgical pathology
• 作者: Agaimy A;Fonseca I;Martins C;Thway K;Barrette R;Harrington KJ;Hartmann A;French CA;Fisher C
• 通讯作者: Fisher C

NUT Carcinoma Without Upfront Surgical Resection: A Case Report.

• DOI: 10.1097/mph.0000000000001865
• 发表时间: 2021-07-01
• 期刊: Journal of pediatric hematology/oncology
• 作者: Leeman R;Pinkney K;Bradley JA;Ruiz R;DuBois SG;French C;Trucco M
• 通讯作者: Trucco M

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

• DOI: 10.1158/2159-8290.cd-15-1335
• 发表时间: 2016-05
• 期刊: Cancer discovery
• 影响因子: 28.2
• 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
• 通讯作者: French CA

NUT carcinoma, an under-recognized malignancy: a clinicopathologic and molecular series of 6 cases showing a subset of patients with better prognosis and a rare ZNF532::NUTM1 fusion.

NUT 癌，一种未被充分认识的恶性肿瘤：6 例临床病理学和分子系列显示部分患者预后较好，且存在罕见的 ZNF532::NUTM1 融合。

• DOI: 10.1016/j.humpath.2022.05.015
• 发表时间: 2022
• 期刊: Human pathology
• 影响因子: 3.3
• 作者: Abreu,RodrigoFonseca;Oliveira,ThiagoBuenode;Hertzler,Hans;Toledo,RonaldoNunes;D'AlmeidaCosta,Felipe;LopesPinto,ClóvisAntonio;Nunes,WarleyAbreu;Nascimento,AlessandraF;French,ChristopherAlexander;Nascimento,AntonioGeraldo
• 通讯作者: Nascimento,AntonioGeraldo

Exceptional Response to Bromodomain and Extraterminal Domain Inhibitor Therapy With BMS-986158 in BRD4-NUTM1 NUT Carcinoma Harboring a BRD4 Splice Site Mutation.

使用 BMS-986158 在含有 BRD4 剪接位点突变的 BRD4-NUTM1 NUT 癌中对溴结构域和末端结构域抑制剂治疗有特殊反应。

• DOI: 10.1200/po.22.00633
• 发表时间: 2023
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Cheng,MichaelL;Huang,Yeying;Luong,Nhi;LoPiccolo,Jaclyn;Nishino,Mizuki;Sholl,LynetteM;Chirieac,LucianR;Santucci,AlisonD;Rabin,MichaelS;Jänne,PasiA;Coker,Shodeinde;Diamond,JenniferR;Hilton,John;Shapiro,GeoffreyI;French,C
• 通讯作者: French,C