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：
10211400
负责人：
JOSEPH KISSIL
金额：
$ 44.13万
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/10211400
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/antagonist 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.

2 型神经纤维瘤病 (NF2) 是一种由 NF2 肿瘤种系突变引起的遗传性疾病抑制基因，其特征是第八脑神经神经鞘瘤的发展。梅林， NF2 基因的产物，在散发性神经鞘瘤、脑膜瘤、室管膜瘤和间皮瘤。尽管过去对该疾病的了解取得了进展几年来，这还没有转化为治疗方法。因此，迫切需要开发 NF2 患者的治疗选择。在分子水平上，Merlin 已被证明具有关键调节作用多种信号转导途径，包括由小 G 蛋白和 Hippo/YAP 调节的信号转导途径途径。为了确定 NF2 缺陷肿瘤的治疗脆弱性，我们评估了 BET 的活性（布罗莫结构域和末端外结构域）蛋白抑制剂 NF2 无效雪旺细胞。 BET 蛋白是其特征是存在两个串联的溴结构域和一个额外的末端结构域。溴结构域可以特异性结合组蛋白上的乙酰化赖氨酸残基，充当破译组蛋白的表观遗传阅读器组蛋白乙酰化代码。我们的初步数据表明 BET 抑制可抑制 NF2- 的增殖培养物中的雪旺细胞和神经鞘瘤细胞和体内肿瘤生长无效，并且这是通过介导的抑制溴结构域蛋白 4 (BRD4)。初步数据表明 BRD4 的作用介导很大程度上是通过 YAP 的监管。重要的是，我们最近证明了 YAP 是加速缺乏 NF2 的雪旺细胞的增殖和肿瘤发生。该提案的目标是鉴定雪旺细胞中 BET 蛋白的基本功能并确定 BET 抑制是否是一种应进一步开发作为 NF2 治疗方式的治疗方法。