The Center for Synovial Sarcoma Biology and Therapeutics

项目概要/摘要 本节与U 54 CA 231638母公司奖励相同。 FusOnC 2滑膜肉瘤生物学和治疗中心的首要目标是开发 并执行一套全面的，多学科的方法植根于蛋白质生物化学， 结构生物学，以确定滑膜肉瘤的机制基础，并揭示机会， 治疗发展该中心的使命与更大的聚变联合会紧密相连 儿童癌症中的癌蛋白以及博·拜登癌症登月计划的目标。的确， 部分原因是我们小组最近发现SS 18-SSX是一种稳定的、整合的 哺乳动物SWI/SNF（BAF）染色质重塑复合物的成员，这是 这个联盟的发展是越来越多的知识，儿科融合癌蛋白， 是特定癌症类型的特征性疾病，通常通过破坏 控制染色质结构和基因控制的蛋白质复合物。我们已经证明，至少 两种融合癌蛋白SS 18-SSX被强调为联盟内的主要重点领域 和EWS-FLI 1，通过BAF复合物特异性地发挥作用，以驱动其癌症特异性致癌基因 表达模式本文综述了BAF多聚体复合物的功能、结构和相互作用的研究进展。 人类癌症类型的遗传研究进一步表明，在所有癌症类型中， 染色质重塑复合物中，编码mSWI/SNF复合物亚单位的基因是最常见的 在所有人类癌症中，超过20%的癌症都发生了突变。 在这里，我们提出了一个多机构，高度协作和多学科的方法，以全面 探究支撑滑膜中SS 18-SSX致癌融合功能的生物学机制， 肉瘤，并使用这些方法中的每一种方法和产生的结果，推出有针对性的治疗 与所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、基因调控和染色质状态;（2） 了解野生型SS 18蛋白在SS 18-SSX融合背景下的作用、其蛋白水平 调节，以及其稳定性可用于治疗益处的机制;（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，特别是那些在染色质结合蛋白质复合物和相关途径。作为一个中心， 每个PI的独特专业知识和研究项目的高度综合性，核心， 合作者提供了最大的可能性，使目标能够成功实现， 新的治疗策略将从这个中心出现。 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