The Center for Synovial Sarcoma Biology and Therapeutics

项目摘要/摘要 本节与U54 CA231638家长奖相同。 FusonC2滑膜肉瘤生物学和治疗中心的总体目标是开发 并执行一套全面的、多学科的方法，植根于蛋白质生物化学和 结构生物学以确定滑膜肉瘤的机制基础并揭示 治疗方面的发展。该中心的使命与更大的聚变联盟的使命紧密相连 儿童癌症中的癌蛋白以及博拜登癌症登月行动的目标。的确， 部分原因是我们小组最近发现了SS18-SSX作为一个稳定和整合的 是哺乳动物SWI/SNF(BAF)染色质重塑复合体的成员，是 该联盟的发展越来越多地认识到，儿科融合癌蛋白 特定癌症类型的病因通常是通过破坏结构和/或活性来发挥作用的吗？ 控制染色质结构从而控制基因控制的蛋白质复合体。我们已经表明，至少 其中两个融合癌蛋白被强调为SS18-SSX联合体中的主要重点领域 和EWS-FLI1，通过BAF复合体特异性作用，驱动其癌症特异性致癌基因 表情模式。生物滤池多聚体及其功能、结构和相互作用的研究 跨人类癌症类型的基因研究进一步表明，在所有 染色质重塑复合体、编码mSWI/SNF复合体亚单位的基因是最多的 经常发生突变，占所有人类癌症的20%以上。 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 SS18-SSX癌基因融合在滑膜中作用的生物学机制探讨 并使用这些方法中的每一种方法和产生的结果进行靶向治疗 与所确定的机制直接相关的发现活动。具体地说，我们的方法 包括三个主要领域：(1)BAF复合体靶向、基因调控和染色质状态；(2) 了解野生型SS18蛋白在SS18-SSX融合中的作用，其蛋白水平 调节，以及其稳定性可用于治疗的机制；(3)使用 基因组规模的遗传扰动策略，以发现和机械地表征SS特异性 脆弱性，特别是染色质结合蛋白复合体和相关途径中的脆弱性。作为一个中锋， 每个PI的独特专业知识以及研究项目、核心和 合作者提供了成功实现目标的最大可能可能性，并且 新的治疗策略将从该中心涌现出来。 项目摘要/摘要第69页

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. Project Summary/Abstract Page 69