Sizing up a weakness in synovial sarcoma’s genes

In the sport of sumo, a bout most commonly ends when one competitor is pushed or thrown outside of a ring of straw bales partially buried in clay. New research shows that using a drug as a blocker to outcompete the SUMO2 protein may be a winning strategy against an aggressive cancer called synovial sarcoma.

Synovial sarcoma tumors begin growing in the body's soft tissues such as muscles or ligaments, often near large joints such as the knees. This rare cancer accounts for 800-1,000 cases each year in the United States and occurs most often in adolescents and young adults.

While most patients with synovial sarcoma are diagnosed before the cancer has spread from the original tumor, up to nearly one in five are diagnosed with more advanced metastatic disease. Once synovial sarcoma has spread, it is much more difficult to treat. Due to its propensity to metastasize to the lungs and a lack of targeted treatments, this disease has a five-year survival rate of roughly 50-60%.

Scientists at Sanford Burnham Prebys Medical Discovery Institute and their collaborators at the University of California Los Angeles, University of California San Diego and University of Edinburgh published findings August 13, 2025, in The European Molecular Biology Organization (EMBO) Journal demonstrating the use of public genomic screening data to identify and study a new genetic vulnerability that may help improve treatment options for synovial sarcoma.

The research team began by analyzing data from the Dependency Map (DepMap) Consortium’s efforts to accelerate precision cancer medicine by finding genes required for cell growth in many types of cancer. The investigators used this data to create a list of genes that had been found to be more essential for synovial sarcoma cells to grow than for other cancer cells.

Then, the scientists compared this list of genes with the results of parallel experiments on synovial sarcoma cells in a dish and on mice. These experiments also sought to locate genes that synovial sarcoma cells depend on for viability and growth. By comparing the lists of genes from the public datasets, cell culture and animal model screening experiments, the team was able to narrow down the genes most likely to be selectively essential for synovial sarcoma.

The researchers compared this more concise set of genes with data on genes influenced by the protein created due to synovial sarcoma’s unique mutation. In synovial sarcoma cells, the abnormal swapping of two genes causes the cells to produce the SS18::SSX fusion oncoprotein that drives the cells’ cancerous identity. Once the screening data was examined alongside genes affected by this cancer-causing protein, the SUMO2 gene stood out. This gene, which contains the instructions for the small ubiquitin-like modifier 2 protein, was considered among the most essential in the screens of cell culture and mice, and it was shown in prior research to be activated by the SS18::SSX fusion oncoprotein.

To follow up on these findings, the scientists tested the effects of using a small molecule called TAK-981 to block the SUMO2 protein. Treatment with this SUMO2 inhibitor impaired the growth of synovial sarcoma cells and reduced the activity of genes associated with the cells’ cancerous identity, including genes hijacked by the SS18::SSX fusion oncoprotein to accelerate cell growth. Additional experiments further demonstrated that SUMO2 inhibition reduced the levels of the SS18::SSX fusion oncoprotein.

“Developing more targeted therapies for synovial sarcoma has been hampered by our limited understanding of the mechanisms that drive disease onset and progression,” said Rema Iyer, PhD, a recent graduate of the Sanford Burnham Prebys Graduate School of Biomedical Sciences and lead author of the manuscript.

“Our results reveal that SUMO2 inhibition is an attractive therapeutic strategy in synovial sarcoma,” said Ani Deshpande, PhD, a professor in the Sanford Burnham Prebys Cancer Genome and Epigenetics Program and the study’s senior and corresponding author.

“SUMO2 inhibitors may work even more effectively in combination with chemotherapy, and our findings suggest that TAK-981 is a strong candidate for clinical testing especially given prior preclinical studies in acute myeloid leukemia and pancreatic cancer.”

Additional authors include:

• Anagha Deshpande, Aditi Pedgaonkar, Pramod Akula Bala, Darren Finlay, Kristiina Vuori and Rabi Murad from Sanford Burnham Prebys
• Taehee Kim and Alice Soragni from the University of California Los Angeles
• Gerard L Brien from the University of Edinburgh
• Hiromi I Wetterstein from the University of California San Diego

The study was supported by the National Institutes of Health and National Cancer Institute.

The study’s DOI is 10.1038/s44318-025-00526-w.