Research Project
10381956
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.
