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。癌症基因组地图集报告了黑色素瘤的高突变负荷。 “驱动器”基因和新型治疗剂的识别仍然是主要重点。值得注意的是，有必要根据具有治疗意义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带来新的治疗疗法，并根据遗传特征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突变确定为一种新的遗传事件。 FBXW7是一个编码F-box蛋白家族成员的肿瘤抑制基因。 F-box蛋白构成了称为SCFS（SKP1-Cullin-F-box）的泛素蛋白连接酶复合酶的四个亚基之一，该蛋白在磷酸化依赖性泛素化中起作用，并调节具有核心蛋白网络在细胞分裂，细胞生长和分化中具有中心作用。 FBXW7的底物包括良好的癌蛋白，其中之一是Notch1。黑色素瘤样品的筛查显示FBXW7中的错义和无义突变，其中一些是经常出现的。我们发现，在人黑色素瘤细胞系中FBXW7的沉默导致Notch1水平升高。此外，我们表明具有FBXW7下调调节的异种移植肿瘤对Notch信号抑制有反应。在此提案中，我们旨在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Notch1抑制的治疗益处。该提案中的研究旨在扩大我们对影响黑色素瘤发育和转移的遗传事件的知识，目的是确定新的目标，以实现未来机制驱动的临床试验。这些研究的最终目的是将从分子研究获得的知识转化为可用于临床决策的工具。