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.

项目总结/文摘