Reversing the Oncogenic Roles of Misdirected Chromatin Remodeling in Synovial Sarcoma
Synovial sarcoma (SS) represents the most common non-rhabdomyosarcomatous soft-tissue malignancy in pediatric patients; 30% of all synovial sarcomas 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 forms of treatment, underscoring the need for an understanding of their pathogenesis and the development of disease-specific biologic agents which target the molecular hallmark, the SS18-SSX fusion protein, or its interactions.
SS tumors are uniformly characterized (essentially 100% of patients) by the t(x;18) chromosomal translocation which causes the addition of precisely 78 amino acids of the SSX protein to SS18, which I recently identified and characterized as a subunit of a chromatin remodeling complex known as the mSWI/SNF or BAF complex. BAF complexes use the energy of ATP hydrolysis to remodel chromatin (our genetic material, DNA, and its protein scaffold) to allow for timely and appropriate gene expression. I recently demonstrated that the SS18-SSX fusion preferentially binds to and disrupts the composition and function of these complexes, favoring tumor development. Remarkably, I have found that this is dynamic and reversible; normal complexes can be reformed and proliferation of synovial sarcoma cells is ceased upon re-integration of wild-type SS18 or destabilization of the binding of the SS18-SSX fusion protein to BAF complexes. The work proposed herein has strong potential to lead to the development of a highly specific, targeted therapeutic for this intractable cancer.