Reversing mSWI/SNF (BAF) Complex Misassembly and Genomic Targeting in Human Synovial Sarcoma
Background: Synovial sarcoma (SS) represents the most common non-rhabdomyosarcomatous soft-tissue malignancy in pediatric patients; 30% of all SS manifest during the first two decades of life with a median age of 13 years. These aggressive tumors are largely resistant to conventional chemotherapy-based treatments, underscoring the need to understand the disease development and identify therapeutic approaches. SS tumors are uniformly characterized (essentially 100% of patients) by a genetic event called chromosomal translocation which results in two proteins being abnormally fused together. This translocation causes the addition of a segment of a protein called “SSX” to a protein called “SS18,” which is a member of a large protein complex in the nucleus of our cells called the BAF complex. BAF complexes function to alter the architecture of our genomes and allow for timely and appropriate gene expression.
Project Goal: We recently demonstrated that the SS18-SSX fusion preferentially binds to and disrupts the composition and function of these complexes, favoring tumor development. Remarkably, we have found that this is dynamic and reversible; normal complexes can be reformed and proliferation is ceased if SSX and its interactions are blocked. The work proposed will provide novel insights regarding the mechanism underlying SS18-SSX-mediated activity and has potential to lead to the development of highly specific targeted therapeutics for this intractable cancer.
Project Update 2022: During the 4-year term of the ALSF ‘A’ Award, we have made significant progress on both of our key aims. Specifically, we have mapped, for the first time, the SS18-SSX fusion oncoprotein, which is the driver of disease, on the genome to understand which genes and which types of chromatin environments inside the nucleus of the cell it targets. Defining the localization of the SS18-SSX fusion has provided new understanding regarding the mechanisms of oncogenic gene expression and maintenance of cell proliferation in synovial sarcoma. Such results ultimately led us to define the BRD9-containing ncBAF complex as the top dependency in SS cell lines, which has prompted the development of new clinical trials (FHD-609 (degradation of BRD9) in relapsed/refractory human SS). This is a major milestone currently under evaluation in Phase I clinical studies. Further, we have used these data to dissect, down to a structural level, the way in which SS18-SSX (or, the SSX 78aa tail (which drives disease)) binds to chromatin. Defining this in 3D structural detail will position us to identify new peptide- and small molecule-based approaches that are on target and specifically inhibit the interaction of SS18-SSX fusion oncoprotein with the genomic landscape.
