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Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer

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Abstract

Patients afflicted with synovial sarcoma share the fate of other translocation positive sarcomas; the driver mutation for this cancer is known, yet no means to target the fusion protein SS18-SSX directly exist. Current chemotherapeutic regimens are minimally beneficial, particularly in patients with metastatic disease. SS18-SSX putatively promotes its oncogenic activity through protein-protein interactions that alter genetic programs through chromatin remodeling. This review discusses the functional protein network of SS18-SSX, both wild-type and fusion protein, considers its intrinsically disordered nature, and provides insights into potential therapeutic strategies. A comprehensive overview of the clinical characteristics reveals the need for newly targeted therapeutics based upon oncogenic transformation by the fusion protein SS18-SSX. The wild-type, non-fused proteins SS18 and SSX are presented including their molecular structure and biological function with regard to protein-protein interactions. The interactions of the wild-type proteins inform the oncogenic changes of the fusion protein. The SS18-SSX fusion protein and its protein interactions are described and evaluated for their biological consequences that lead to oncogenesis. This review illustrates the key protein interactions of SS18-SSX that may qualify as primary targets for small molecule-based disruption leading to the development of SS18-SSX-specific drugs. These novel targeted therapeutics may provide a specificity that ultimately improves survival while reducing morbidity of patients with synovial sarcoma.

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Acknowledgments

The authors would like to thank Cigall Kadoch, Ph.D., Harvard University, for her critical review and feedback on this manuscript. Support for this work has come from the Children’s Cancer Foundation, Baltimore, MD, St. Baldrick’s Foundation, Burroughs Wellcome Clinical Scientist Award in Translational Research (to J.A.T.), and Mildred-Scheel-Postdoktoranden-Programm of Deutsche Krebshilfe (to S.K.Z.), and NIH Grants R01CA133662 (to J.A.T.), R01CA138212 (to J.A.T.)

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  1. Department of Oncology, Georgetown University, Research Building, Suite E501, 3970 Reservoir Road, N.W., Washington, DC, 20057, USA

    Stefan K. Zöllner & Jeffrey A. Toretsky

  2. Department of Pediatrics, Georgetown University, Research Building, Suite E501, 3970 Reservoir Road, N.W., Washington, DC, 20057, USA

    Jeffrey A. Toretsky

  3. Department of Pediatric Hematology and Oncology, University Childrens Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany

    Stefan K. Zöllner & Claudia Rössig

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  1. Stefan K. Zöllner
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Correspondence to Jeffrey A. Toretsky.

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Zöllner, S.K., Rössig, C. & Toretsky, J.A. Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer. Cancer Metastasis Rev 34, 417–428 (2015). https://doi.org/10.1007/s10555-015-9575-z

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