NOTCH inhibition in melanoma

黑色素瘤中的 NOTCH 抑制

基本信息

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
项目类别：
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

项目摘要

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”基因的识别和新疗法仍然是主要焦点。值得注意的是，需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引入新的治疗方法，并根据基因图谱对患者进行分层治疗。我们通过转移性黑色素瘤的外显子组测序将 FBXW7 突变鉴定为一种新的遗传事件。 FBXW7 是一种肿瘤抑制基因，编码 F-box 蛋白家族的成员。 F-box 蛋白构成泛素蛋白连接酶复合物 SCF (SKP1-cullin-F-box) 的四个亚基之一，其在磷酸化依赖性泛素化中发挥作用，并调节在细胞分裂、细胞生长中发挥核心作用的蛋白质网络。和差异化。 FBXW7 的底物包括已充分表征的癌蛋白，其中之一是 NOTCH1。对黑色素瘤样本的筛查发现 FBXW7 存在错义和无义突变，其中一些突变是反复出现的。我们发现人类黑色素瘤细胞系中 FBXW7 的沉默会导致 NOTCH1 水平升高。此外，我们发现 FBXW7 下调的异种移植肿瘤对 NOTCH 信号传导抑制有反应。在本提案中，我们的目标是研究人类黑色素瘤中发现的 FBXW7 突变的影响以及在这种情况下抑制 NOTCH1 的治疗益处。该提案中的研究旨在扩展我们对影响黑色素瘤发展和转移的遗传事件的了解，目的是为未来机制驱动的临床试验确定新靶点。这些研究的最终目标是将分子研究中获得的知识转化为可用于临床决策的工具。