Validation of EP400 downstream effectors and potential therapeutic targets in Merkel cell carcinoma

默克尔细胞癌中 EP400 下游效应器和潜在治疗靶点的验证

基本信息

批准号：
10017929
负责人：
Jingwei Cheng
金额：
$ 16.39万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017929
关键词：
Antigens Area Automobile Driving Binding Proteins CUL9 gene Cell physiology Chromatin Complex DNA Tumor Viruses Disease FOXM1 gene Family member GLMN gene Human Laboratories Large T Antigen MYCL1 gene Malignant Neoplasms Merkel Cells Merkel cell carcinoma Mus Mutate Mutation Oncogenic Oncogenic Viruses Oncologist Oncoproteins Polyomavirus Polyomavirus Transforming Antigens Population Process Proteins Regulator Genes Reporting Research Retinoblastoma Protein Role Simian virus 40 Skin Cancer Specialist Symptoms System Testing Time Training Tumor Antigens Tumor Suppressor Proteins Validation Viral Viral Antigens Viral Proteins Virus anticancer research cancer genome graduate student human disease insight melanoma mouse model neuroendocrine cancer novel novel therapeutics programs recruit small molecule inhibitor success therapeutic target tumorigenesis

项目摘要

PROJECT SUMMARY The role of Human Oncogenic Viruses in Cancer Research Tumor viruses are widely spread in human population and are reported to cause 20% of human cancers. The DNA Tumor Viruses express viral oncoproteins that can specifically target the central nodes of host cellular networks. Cellular proteins targeted by tumor viruses are often mutated even in non-viral cancers and very likely to be driving factors of tumorigenesis. While cancer research is normally perplexed by tens of thousands of passenger mutations that reside in cancer genomes, compact small DNA tumor viruses have provided advantages for oncologists to focus on a few viral proteins to dissect gene regulatory networks in cancer. James DeCaprio identified Retinoblastoma Protein (RB1) as the first tumor suppressor using simian polyomavirus SV40 together with three other groups. Using this approach with continued success, the DeCaprio laboratory has continued to discover important cellular proteins by identifying SV40 and more recently Merkel cell polyomavirus T antigen associated proteins. Using SV40 Large T antigen, the DeCaprio laboratory identified CUL7, CUL9, GLMN, FBWX8, FAM111A, the mammalian DREAM complex and the MuvB-FoxM1 complex. These novel binding proteins regulate critical cellular processes, and some are involved in human diseases. More recently, the DeCaprio laboratory has focused on Merkel cell polyomavirus (MCPyV) and its contribution to the highly aggressive Merkel cell carcinoma (MCC). Although MCPyV can infect more than 90% of the global population, it typically does not cause any symptoms. However, MCPyV can cause MCC, a disease several times more lethal than melanoma. Given the oncogenic potential of this widespread virus, it is important for us to understand the functions of human polyomavirus viral antigens and their contribution to cancer. Research Specialist’s Activity/Effort: Recently, we gained novel insight into the mechanisms of tumorigenesis in MCC. We discovered that MCPyV small tumor antigen (ST) recruits L-MYC (MYCL) to the EP400 chromatin complex to drive essential oncogenic processes. I will continue to contribute to the success of Dr. DeCaprio’s research program in the following areas: (1) Identify downstream targets of ST-MYCL-EP400 complex that are required in tumorigenesis; (2) Identify therapeutic targets in MCC and test small molecule inhibitors that may inhibit the viability of MCPyV positive MCC; (3) Generate a mouse model of MCC with targeted integration of MCPyV tumor antigens into a mouse safe harbor locus. My roles include both direct scientific contributions as well as specific training of graduate students and technicians in the DeCaprio laboratory.

项目概要人类致癌病毒在癌症研究中的作用肿瘤病毒在人群中广泛传播，据报道导致 20% 的人类癌症。 DNA肿瘤病毒表达可以特异性靶向宿主中央节点的病毒癌蛋白肿瘤病毒靶向的细胞蛋白即使在非病毒癌症中也经常发生突变。很可能是肿瘤发生的驱动因素，而癌症研究通常被数十个因素所困扰。癌症基因组中存在数千个突变乘客，紧凑的小DNA肿瘤病毒具有为肿瘤学家提供了关注一些病毒蛋白来剖析基因调控网络的优势 James DeCaprio 发现视网膜母细胞瘤蛋白 (RB1) 是第一个使用猿猴的肿瘤抑制因子。多瘤病毒 SV40 与其他三个小组一起使用这种方法并取得了持续的成功。 DeCaprio 实验室通过鉴定 SV40 等继续发现重要的细胞蛋白最近默克尔细胞多瘤病毒T抗原相关蛋白使用SV40大T抗原，DeCaprio。实验室鉴定出 CUL7、CUL9、GLMN、FBWX8、FAM111A、哺乳动物 DREAM 复合体和 MuvB-FoxM1 复合物调节关键的细胞过程，其中一些是与人类疾病有关。最近，DeCaprio 实验室重点研究默克尔细胞多瘤病毒 (MCPyV) 及其尽管 MCPyV 可以感染 90% 以上，但仍会导致高度侵袭性默克尔细胞癌 (MCC)。对于全球人口来说，它通常不会引起任何症状，但是 MCPyV 可导致 MCC（一种 MCC）。鉴于这种广泛传播的病毒的致癌潜力，这种疾病的致死率是黑色素瘤的几倍。对于我们了解人类多瘤病毒病毒抗原的功能及其贡献非常重要癌症。研究专家的活动/努力：最近，我们对 MCC 肿瘤发生机制有了新的认识。 MCPyV 小肿瘤抗原 (ST) 将 L-MYC (MYCL) 招募到 EP400 染色质复合物以驱动必需的我将继续为德卡普里奥博士的研究项目的成功做出贡献。以下领域： (1) 确定 ST-MYCL-EP400 复合物下游目标，这些目标是 (2) 确定 MCC 的治疗靶点并测试可能抑制 MCC 的小分子抑制剂 MCPyV 阳性 MCC 的活力；(3) 生成具有 MCPyV 靶向整合的 MCC 小鼠模型我的职责包括直接的科学贡献和科学贡献。在迪卡普里奥实验室对研究生和技术人员进行专门培训。