Targeting BET-bromodomains in neuroblastoma

靶向神经母细胞瘤中的 BET-溴结构域

• 批准号: 9066220
• 负责人: Kimberly Stegmaier
• 金额: $ 66.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066220
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acetylation; Adult; BRD2 gene; Binding; Binding Sites; Biological Assay; Biological Markers; Bromodomain; Bypass; Cancer cell line; Cells; ChIP-seq; Child; Childhood; Childhood Extracranial Solid Tumor; Chromatin; Clinical; Clinical Trials; Combined Modality Therapy; DNA; DNA Binding; Data; Development; Disease; EZH2 gene; Epigenetic Process; Family member; Future; Gene Expression Profile; Genes; Genetic Markers; Genetic Transcription; Genetically Engineered Mouse; Genomics; Health; Histones; Human; Link; Lysine; MYC Family Protein; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Massive Parallel Sequencing; Measures; Mediator of activation protein; N-Myc Protein; Neuroblastoma; Open Reading Frames; Pathway interactions; Patients; Pharmaceutical Preparations; Polycomb; Protein Binding Domain; Protein Methyltransferases; Proto-Oncogene Proteins c-myc; Publishing; Recruitment Activity; Repression; Resistance; Resistance development; Role; Route; Sampling; Solid Neoplasm; Tertiary Protein Structure; Testing; Tissues; Transcription Coactivator; Transcriptional Activation; Translations; Xenograft procedure; aurora kinase; base; chemotherapy; chromatin immunoprecipitation; chromatin protein; epigenome; high risk; histone methyltransferase; in vivo; inhibitor/antagonist; mouse model; neuroblastoma cell; new technology; pre-clinical; preclinical trial; programs; protein complex; research study; resistance mechanism; response; screening; small hairpin RNA; standard of care; targeted agent; therapy resistant; tumor

 DESCRIPTION (provided by applicant): MYC transcription factors are frequently dysregulated in cancer. Chromatin-associated protein complexes link MYC to increased histone lysine acetylation in the epigenome. Bromodomain and extraterminal domain (BET) proteins, which bind to these acetylated histone lysines and recruit MYC protein, have therefore emerged as compelling targets in cancer, with inhibitors entering clinical trials. Neuroblastoma is the most common extracranial solid tumor of childhood, with high-risk disease frequently showing Amplification of MYCN. We performed an unbiased screen of diverse cancer cell lines for sensitivity to BET bromodomain inhibitors (BETi). We validated the activity of both BRD4-directed shRNA and BETi against MYCN-amplified neuroblastoma cells, extending these studies in vivo both to patient derived xenografts (PDX) and to genetically engineered mouse (GEM) models of MYCN-driven neuroblastoma. Importantly, while BETi showed remarkable efficacy in vivo, they were not curative, suggesting the need for combination therapies. We hypothesize tat BETi block interactions of MYCN with the epigenetic machinery, and that combination therapies incorporating BETi represent a robust, translatable approach to enhance efficacy, and block emergent resistance in MYCN-driven NB. Our proposal identifies A) Mechanisms through which blockade of MYCN interferes with transformation, B) Mechanisms by which tumors develop resistance to BETi, and C) Translatable combination therapies to block emergent resistance. Successful completion guides effective clinical translation of BETi as pathway-specific inhibitors of MYCN. Aim 1: To clarify a role for EZH2 as a mediator of response to BETi, in MYCN-driven neuroblastoma. Aim 2: To test BETi with EZH2i, and with other translatable combination therapies in preclinical trials in neuroblastoma. Aim 3: To guide development of additional effective combination therapies, by identifying emergent mechanisms for resistance.

 描述(申请人提供)：MYC转录因子在癌症中经常失控。染色质相关蛋白复合体将MYC与表观基因组中增加的组蛋白赖氨酸乙酰化联系在一起。溴结构域和端外结构域(BET)蛋白与这些乙酰化组蛋白赖氨酸结合，并招募MYC蛋白，因此成为癌症的引人注目的靶点，抑制剂进入临床试验。神经母细胞瘤是儿童最常见的颅外实体瘤，其高危疾病常表现为MYCN扩增。我们对不同的癌细胞株进行了对BET溴域抑制剂(Beti)敏感性的无偏筛查。我们验证了BRD4导向的shRNA和Beti对MYCN扩增的神经母细胞瘤细胞的活性，将这些研究在体内扩展到患者来源的异种移植(PDX)和MYCN驱动的神经母细胞瘤的基因工程小鼠(GEM)模型。重要的是，尽管Beti在体内显示了显著的疗效，但它们并不是治愈的，这表明需要联合治疗。我们假设Tat Beti阻断了MYCN与表观遗传机制的相互作用，并且结合Beti的联合疗法代表了一种强大的、可翻译的方法来提高疗效，并阻止MYCN驱动的NB的新出现的耐药。我们的建议确定了A)阻断MYCN干扰转化的机制，B)肿瘤对Beti产生耐药性的机制，以及C)可翻译的联合疗法来阻断新出现的耐药性。成功的完成指导了Beti作为MYCN途径特异性抑制物的有效临床翻译。目的1：阐明EZH2在MYCN驱动的神经母细胞瘤中作为对Beti反应的中介的作用。目的2：在神经母细胞瘤的临床前试验中，用EZH2和其他可翻译的联合疗法测试Beti。目的3：通过确定耐药的紧急机制，指导其他有效的联合疗法的开发。