Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets

阐明神经纤维瘤病的表观遗传景观和治疗靶点的开发

• 批准号: 10473771
• 负责人: JOSEPH KISSIL
• 金额: $ 42.32万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473771
• 关键词: ATAC-seq; Acoustic Nerve; Animal Model; Antineoplastic Agents; Binding; Bromodomain; Cell Differentiation process; Cell Proliferation; Cells; ChIP-seq; Clinical Trials; Code; Contact Inhibition; Data; Development; Disease; Down-Regulation; Ensure; Ependymoma; Epigenetic Process; Family; Frequencies; Genes; Genetic Transcription; Genomics; Germ-Line Mutation; Goals; Growth; Hereditary Disease; Histone Acetylation; Histones; Impairment; Inherited; Loss of Heterozygosity; Lysine; Malignant Neoplasms; Mediating; Mesothelioma; Modality; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mutate; Mutation; Nervous System Neoplasms; Nervous system structure; Neurilemmoma; Neurofibromatoses; Neurofibromatosis 2; Neurofibromin 2; Normal Cell; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Proteins; Reader; Receptor Protein-Tyrosine Kinases; Regulation; Resolution; Role; Schwann Cells; Signal Pathway; Signal Transduction Pathway; Technology; Tertiary Protein Structure; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Translating; Tumor Suppressor Genes; base; cancer cell; cancer type; epigenomics; in vivo; inhibitor; interest; meningioma; neoplastic cell; prevent; programs; protein function; ras Proteins; research clinical testing; small molecule; small molecule inhibitor; synergism; targeted treatment; therapeutic development; therapeutic target; transcriptome sequencing; tumor; tumor growth; tumorigenesis; virtual

Neurofibromatosis type 2 (NF2) is an inherited disorder caused by germ line mutations of the NF2 tumor suppressor gene and is characterized by development of schwannomas of the VIIIth cranial nerve. Merlin, the product of the NF2 gene, is also inactivated to a significant extent in sporadic schwannomas, meningioma, ependymoma and mesothelioma. In spite of progress made in the understanding of the disease over the past several years, this has not yet translated into therapies. Thus, there is an urgent and unmet need to develop therapeutic options for NF2 patients. At a molecular level, Merlin has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hippo/YAP pathway. In an effort to identify therapeutic vulnerabilities in NF2-deficient tumors, we assessed the activity of the BET (Bromodomain and Extra-Terminal domain) protein inhibitors NF2-null Schwann cells. The BET proteins are characterized by the presence of two tandem bromodomains and an extra-terminal domain. The bromodomains can specifically bind acetylated lysine residues on histones, serving as epigenetic readers that decipher the histone acetylation code. Our preliminary data indicate that BET inhibition suppresses the proliferation of NF2- null Schwann and schwannoma cells in culture and tumor growth in vivo, and that this is mediated through inhibition of bromodomain protein 4 (BRD4). Preliminary data indicates that the effects of BRD4 are mediated to a significant extent via regulation of YAP. Importantly, we recently demonstrated that YAP is required for the accelerated proliferation of NF2-deficient Schwann cells and tumorigenesis. The goals of this proposal are to identify the essential functions of BET proteins in Schwann cells and determine whether BET inhibition is a therapeutic approach that should be further developed as a treatment modality for NF2.

神经纤维瘤病2型（NF2）是由NF2肿瘤的种系突变引起的遗传疾病 抑制基因，其特征在于颅神经的schwannomas的发展。梅林， NF2基因的产物在孢子瘤，脑膜瘤，脑膜炎，脑膜瘤，也很大程度地被灭活 膜瘤和间皮瘤。尽管过去对疾病的理解取得了进步 几年，这尚未转化为疗法。因此，有一个紧迫而没有满足的发展 NF2患者的治疗选择。在分子水平上，梅林已被证明充当关键调节剂 多个信号转导途径，包括受小G蛋白和河马/YAP调节的途径 路径。 为了确定NF2缺陷肿瘤中的治疗脆弱性，我们评估了BET的活性 （溴结构域和末端结构域）蛋白抑制剂NF2-null schwann细胞。 BET蛋白是 以两个串联溴结构域和一个末端结构域的存在为特征。溴结构域 可以特异性地结合组蛋白上的乙酰化赖氨酸残基，作为表观遗传读取器破译 组蛋白乙酰化代码。我们的初步数据表明，BET抑制会抑制NF2-的增殖 Null Schwann和Schwannoma细胞在体内培养和肿瘤生长中，这是通过 抑制溴结构域蛋白4（BRD4）。初步数据表明BRD4的效果介导 通过调节YAP的很大程度。重要的是，我们最近证明了 NF2缺陷型雪旺细胞和肿瘤发生的加速增殖。该提议的目标是 确定雪旺细胞中BET蛋白的基本功能，并确定BET抑制是否为 应进一步开发为NF2的治疗方式的治疗方法。