Grant: Doctoral: Vanier Canada Graduate Scholarships

Supervisors: Drs. Michael Underhill and Torsten Nielsen, University of British Columbia Synovial sarcoma is an aggressive soft tissue cancer primarily affecting adolescents and young adults and has a 5-year survival rate of less than 10% with disseminated disease. Despite the well-identified causal mutation-fusion of the SS18 gene to the SSX gene-producing a new protein, SS18SSX, current treatments mainly feature surgical resection coupled with radiation therapy and nonspecific cytotoxic chemotherapy. Thus, finding an effective and targeted drug for synovial sarcoma is crucial for improving outcomes and extending the lives of affected young patients. This project will aim to identify novel drug candidates for synovial sarcoma treatment to replace the current clinical standard, Doxorubicin. First, a high-throughput screen involving 3544 FDA-approved drugs was conducted to identify candidates that surpass Doxorubicin's effectiveness in killing synovial sarcoma. We found that 216 (10.4%) of the drugs tested thus far had cell killing or growth blocking effects and lower toxicity than Doxorubicin. These drugs will be tested for comprehensive effectiveness using additional patient-derived synovial sarcoma cell lines in a 3D spheroid culture. Finally, successful drugs which target synovial sarcoma cells while sparing noncancerous human cells will be tested in a mouse model of synovial sarcoma. By genetically engineering mouse connective tissue stem cells to make SS18SSX, we have a novel mouse model that closely recapitulates the disease seen in humans. All mutant mice develop synovial sarcoma at 15.5 weeks of age, demonstrating the reproducibility and the strong effects of this mutation. By conducting the first large-scale screen in synovial sarcoma using FDA-approved drugs, we anticipate that our results should be readily translatable to the clinic, representing a significant step towards improving the therapeutic options available for this challenging malignancy.