The Center for Synovial Sarcoma Biology and Therapeutics Abstract 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 and the Beau Biden Cancer Moonshot Initiative. A major impetus for the development of this Consortium has been the growing knowledge that 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, bind and act via BAF complexes to drive cancer-specific oncogenic gene expression. Importantly, genetic studies across human cancer types have indicated that genes encoding encoding mSWI/SNF complex subunits are among the most frequently mutated, at over 20% of all human cancers, further underscoring the need for a detailed understanding of BAF complex structure, topology and mechanisms on chromatin. Our multi-institutional collaborative network seeks to comprehensively interrogate biologic mechanisms underpinning the function of the SS18-SSX oncogenic fusion protein in synovial sarcoma and to use the 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 genomic targeting, gene regulation, and chromatin state interactions, including interactions with other chromatin regulators; (2) Understanding the role of the wild-type SS18 protein, its protein-level regulation, and mechanisms by which its stabilization can reverse SS18-SSX-mediated BAF complex activity and be exploited for therapeutic benefit; (3) Mechanistically characterizing synovial sarcoma-specific vulnerabilities, centered in chromatin-bound protein complexes and related pathways. The highly integrative nature of the PI-directed research projects and expertise within collaborator laboratories provide the strongest possible likelihood that the aims will be successfully achieved and that novel therapeutic strategies will emerge from this Center.
Synovial sarcoma is a highly aggressive soft-tissue cancer for which there exist no effective targeted therapeutic approaches despite the pathognomonic, genomically well-defined molecular lesion hallmark to every case: the SS18-SSX fusion. Understanding the function of the SS18-SSX fusion in the context of the macromolecular machine to which it binds and hijacks, as well as the features of the chromatin landscape which are uniquely permissive of these activities, represent the most critical next steps and are at present major barriers to therapeutic progress. Our Center on Synovial Sarcoma Biology and Therapeutics seeks to challenge existing paradigms, efficiently define the underlying biology, and to present the field with novel, highly-specific targeted therapeutics to combat this aggressive and devastating disease.
