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

基本信息

批准号：
10680527
负责人：
JOSEPH KISSIL
金额：
$ 41.14万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
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/10680527
关键词：
ATAC-seq Acceleration Acetylation 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 Lines Goals Growth Hereditary Disease Histone Acetylation Histones Impairment Inherited Loss of Heterozygosity Lysine Malignant Neoplasms Mediating Mesothelioma Modality Molecular Monomeric GTP-Binding Proteins Mutate Mutation Nervous System Nervous System Neoplasms Neurilemmoma Neurofibromatoses Neurofibromatosis 2 Neurofibromin 2 Normal Cell Output Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Play Proliferating 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 autosome 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

项目摘要

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。