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

• 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
• 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

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 蜂窝网络。即使在非病毒性癌症中，肿瘤病毒靶向的细胞蛋白也经常发生突变 很可能是肿瘤发生的驱动因素。虽然癌症研究通常会被数十个问题所困扰 癌症基因组中存在数千个乘客突变，紧凑型小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 癌症。 James DeCaprio 使用猿猴确定视网膜母细胞瘤蛋白 (RB1) 是第一个肿瘤抑制因子 多瘤病毒 SV40 以及其他三个组。使用这种方法并取得持续成功， 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。这些新型结合蛋白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 对高度侵袭性默克尔细胞癌（MCC）的贡献。虽然MCPyV可以感染90%以上 就全球人口而言，它通常不会引起任何症状。然而，MCPyV 可导致 MCC， 这种疾病的致死率是黑色素瘤的几倍。鉴于这种广泛传播的病毒具有致癌潜力， 对于我们了解人类多瘤病毒病毒抗原的功能及其对 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。我们发现 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 致癌过程。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 肿瘤发生； (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) 通过定向整合MCPyV生成MCC小鼠模型 肿瘤抗原进入小鼠安全港位点。我的角色包括直接的科学贡献以及 在迪卡普里奥实验室对研究生和技术人员进行专门培训。