NOTCH inhibition in melanoma

黑色素瘤中的 NOTCH 抑制

• 批准号: 8883428
• 负责人: Julide T. Celebi
• 金额: $ 18.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883428
• 关键词: Acceleration; BRAF gene; Binding; Biological; Cell Differentiation process; Cell Line; Cell division; Clinical Trials; Colon; Complex; Cullin Proteins; Development; Down-Regulation; Drug resistance; Endometrium; Event; F Box Domain; F-Box Proteins; FBXW7 gene; Frequencies; Future; Genes; Genetic; Genomics; Goals; Health; Hematologic Neoplasms; Heterogeneity; High-Throughput Nucleotide Sequencing; Human; In Vitro; Knowledge; Lead; Lung; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Missense Mutation; Molecular; Molecular Genetics; Molecular Profiling; Molecular Target; Mutation; NOTCH1 gene; Neoplasm Metastasis; Nonsense Mutation; Oncogene Proteins; Pathogenesis; Patients; Phenotype; Phosphorylation; Pre-Clinical Model; Proteins; Recurrence; Reporting; Role; Sampling; Series; Signal Transduction; Small Interfering RNA; Subgroup; System; Testing; The Cancer Genome Atlas; Therapeutic; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; Ubiquitin-Protein Ligase Complexes; Ubiquitination; WD Repeat; Xenograft procedure; base; biliary tract; cell growth; clinical decision-making; cohort; combinatorial; design; exome sequencing; gamma secretase; genetic information; genetic profiling; in vivo; inhibitor/antagonist; insight; interest; meetings; melanocyte; melanoma; member; novel; novel therapeutics; preclinical study; protein degradation; protein expression; research study; screening; success; therapeutic development; therapeutic target; tool; treatment strategy; tumor; tumor growth; tumor xenograft; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Metastatic melanoma is a highly lethal human malignancy. Despite advances in the field, the molecular genetics of melanoma has not been fully characterized. The Cancer Genome Atlas reports high mutational load for melanoma. Identification of 'driver' genes and novel therapeutics remain as a major focus. Notably, there is a need to classify melanomas based on molecular signatures that has therapeutic relevance. Our main goal is to bring in new treatments to the therapeutic arena for melanoma and stratify patients for treatment based on genetic profiles. We identified FBXW7 mutations as a novel genetic event via exome sequencing of metastatic melanomas. FBXW7 is a tumor suppressor gene that encodes a member of the F-box protein family. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination and regulates a network of proteins with central roles in cell division, cell growth and differentiation. The substrates of FBXW7 include well-characterized oncoproteins, one of which is NOTCH1. Screening of melanoma samples revealed missense and nonsense mutations in FBXW7, some of which were recurrent. We found that silencing of FBXW7 in human melanoma cell lines result in elevated NOTCH1 levels. Moreover, we showed that xenograft tumors with FBXW7 down regulation respond to NOTCH signaling inhibition. In this proposal, we aim to study the impact of FBXW7 mutations found in human melanoma and the therapeutic benefit of NOTCH1 inhibition in this setting. The studies in this proposal are designed to expand our knowledge regarding genetic events that influence melanoma development and metastasis with the goal of identifying novel targets for future mechanism-driven clinical trials. The ultimate goal of these studies is to translate knowledge gained from molecular studies into tools that can be used in clinical decision-making.

描述（由申请人提供）：转移性黑色素瘤是一种高度致命的人类恶性肿瘤。尽管该领域取得了进展，但黑色素瘤的分子遗传学尚未得到充分表征。癌症基因组图谱报告了黑色素瘤的高突变负荷。“驱动”基因的鉴定和新的治疗方法仍然是一个主要的焦点。值得注意的是，有必要根据具有治疗相关性的分子特征对黑色素瘤进行分类。我们的主要目标是为黑色素瘤的治疗领域带来新的治疗方法，并根据基因谱对患者进行分层治疗。通过对转移性黑色素瘤的外显子组测序，我们发现FBXW7突变是一种新的遗传事件。FBXW7是一种肿瘤抑制基因，编码F-box蛋白家族的一个成员。F-box蛋白是泛素蛋白连接酶复合物SCFs （SKP1-cullin-F-box）的四个亚基之一，在磷酸化依赖的泛素化中起作用，并调节在细胞分裂、细胞生长和分化中起核心作用的蛋白质网络。FBXW7的底物包括表征良好的癌蛋白，其中一个是NOTCH1。对黑色素瘤样本的筛查显示FBXW7存在错义和无义突变，其中一些是复发性的。我们发现，在人类黑色素瘤细胞系中，FBXW7的沉默导致NOTCH1水平升高。此外，我们发现FBXW7下调的异种移植物肿瘤响应NOTCH信号抑制。在本提案中，我们旨在研究在人类黑色素瘤中发现的FBXW7突变的影响以及NOTCH1抑制在这种情况下的治疗益处。本提案中的研究旨在扩大我们对影响黑色素瘤发展和转移的遗传事件的认识，目的是为未来机制驱动的临床试验确定新的靶点。这些研究的最终目标是将从分子研究中获得的知识转化为可用于临床决策的工具。