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.

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