The Center for Synovial Sarcoma Biology and Therapeutics

滑膜肉瘤生物学和治疗中心

• 批准号: 10381956
• 负责人: Cigall Kadoch
• 金额: $ 19.12万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381956
• 关键词: Architecture; Area; Award; Binding; Binding Proteins; Biological; Biology; Childhood; Chromatin; Chromatin Remodeling Factor; Complex; Development; Disease; EWS-FLI1 fusion protein; Fusion Oncogene Proteins; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic study; Goals; Human; Knowledge; Lesion; Link; Malignant Childhood Neoplasm; Malignant Neoplasms; Mission; Molecular; Mutate; Nature; Oncogenic; Parents; Pathway interactions; Plant Roots; Protein Biochemistry; Proteins; Regulation; Research Project Grants; Role; Structure; Therapeutic; cancer type; collaborative approach; combat; genome-wide; interdisciplinary approach; member; multidisciplinary; novel; novel therapeutic intervention; protein complex; soft tissue; structural biology; synovial sarcoma; targeted treatment; therapeutic development

Project Summary/Abstract This section is unchanged from the U54 CA231638 parent award. The overarching goal of this FusOnC2 Center for Synovial Sarcoma Biology and Therapeutics is to develop and execute a comprehensive, multidisciplinary set of approaches rooted in protein biochemistry and structural biology to define the mechanistic underpinnings of synovial sarcoma and unmask opportunities for therapeutic development. This Center’s mission is tightly aligned with that of the larger Consortium on Fusion Oncoproteins in Childhood Cancers as well as the goals of the Beau Biden Cancer Moonshot Initiative. Indeed, owing in part to our group’s recent findings surrounding the discovery of SS18-SSX as a stable and integrated member of the mammalian SWI/SNF (BAF) chromatin remodeling complex, a major impetus for the development of this Consortium has been the growing knowledge that pediatric fusion oncoproteins that are pathognomonic for specific cancer types often function via disruption of the structure and/or activity of protein complexes that govern chromatin architecture and hence gene control. We have shown that at least two of the fusion oncoproteins highlighted as major areas of emphasis within the Consortium, SS18-SSX and EWS-FLI1, act specifically through BAF complexes to drive their cancer-specific oncogenic gene expression patterns. Study of multimeric BAF complexes and their functions, structure, and interactions are further suggested by genetic studies across human cancer types which have indicated that among all chromatin remodeling complexes, genes encoding mSWI/SNF complex subunits are among the most frequently mutated, at over 20% of all human cancers. Here we present a multi-institutional, highly collaborative and multidisciplinary approach to comprehensively interrogate biologic mechanisms underpinning the function of the SS18-SSX oncogenic fusion in synovial sarcoma and to use each of these approaches and the results generated to launch targeted therapeutic discovery campaigns that are directly linked to the mechanisms identified. Specifically, our approach encompasses three major areas: (1) BAF complex targeting, gene regulation, and chromatin state; (2) Understanding the role of the wild-type SS18 protein in the context of the SS18-SSX fusion, its protein-level regulation, and mechanisms by which its stabilization can be exploited for therapeutic benefit; (3) Using genome-scale genetic perturbation strategies to discover and mechanistically characterize SS-specific vulnerabilities, especially those in chromatin-bound protein complexes and related pathways. As a Center, the unique expertise of each PI and the highly integrative nature of the research projects, cores, and collaborators provide the strongest possible likelihood that the aims will be successfully achieved and that novel therapeutic strategies will emerge from this Center.

项目摘要/摘要 本节与U54 CA231638父级奖没有变化。 该Fusonc2滑膜肉瘤生物学和治疗中心的总体目标是发展 并执行植根于蛋白质生物化学和的全面，多学科的方法 结构生物学来定义滑膜肉瘤的机械基础，并揭露了机会 治疗发展。该中心的任务与融合方面的较大财团的任务紧密相符 儿童癌症中的癌蛋白以及Beau Biden Cancer Moonshot倡议的目标。的确， 部分原因是我们小组的最新发现围绕发现SS18-SSX作为稳定而综合的发现 哺乳动物SWI/SNF（BAF）染色质重塑综合体的成员，这是主要动力 该财团的发展一直是越来越多的知识，即小儿融合癌蛋白 对于特定癌症类型而言，通常会通过破坏结构和/或活动来发挥作用 控制染色质结构并因此控制基因控制的蛋白质复合物。我们已经表明至少 两个融合癌蛋白突出显示为财团内的主要重点区域，SS18-SSX 和EWS-FLI1，专门通过BAF复合物起作用以驱动其癌症特异性致癌基因 表达模式。研究多个BAF复合物及其功能，结构和相互作用是 跨人类癌类型的遗传研究进一步表明，这表明在所有人中 染色质重塑复合物，编码MSWI/SNF复合体亚基的基因是最多的 经常突变，超过20％的人类癌症。 在这里，我们提出了一种多机构，高度协作和多学科的方法，以全面 询问生物学机制，支撑着滑膜中SS18-SSX致癌融合功能的功能 肉瘤并使用这些方法中的每一种以及产生的结果来启动目标疗法 与确定的机制直接相关的发现活动。具体来说，我们的方法 包括三个主要领域：（1）BAF复合物靶向，基因调节和染色质状态； （2） 了解野生型SS18蛋白在SS18-SSX融合的背景下的作用，其蛋白质水平 可以探索其稳定的调节和为治疗益处探索其稳定的机制； （3）使用 基因组规模的遗传扰动策略，以发现和机械表征SS特异性 脆弱性，尤其是染色质结合蛋白复合物和相关途径的脆弱性。作为中心， 每个PI的独特专业知识以及研究项目，核心和高度综合性的性质 合作者提供了成功实现目标的最大可能性，并且 新的热策略将从该中心出现。