Researchers have pinpointed a protein that plays a key role in a type of rare cancer often leading to tumours around joints and tendons, according to new findings in eLife.
Their study in mice suggests that degradation of the BRD9 protein could block tumour progression of synovial sarcoma tumours.
Also known as malignant synovioma, synovial sarcoma is an aggressive soft-tissue sarcoma that can occur anywhere in the body, including the brain, prostate and heart, but often appears near the knee. While it may not cause any noticeable signs or symptoms at first, development of the tumour can cause a lump or swelling and, in some cases, numbness or pain if it presses on nerves.
"Synovial sarcoma tumours contain a characteristic fusion protein, called SS18-SSX, which drives disease development," explains first author and Research Fellow Gerard Brien, who led the research with a team from Scott Armstrong's lab when he was at the Dana-Farber Cancer Institute, US. "Targeting such proteins presents an attractive therapeutic opportunity, but SS18-SSX has previously proven difficult to exploit for drug development purposes."
Using a custom CRISPR/Cas9 screen, Brien and his team identified that the BRD9 protein is critical to the continued growth and survival of synovial sarcoma cells.
"We found that BRD9 is a component of SS18-SSX containing SWI/SNF protein complexes in synovial sarcoma cells," Brien explains. "Moreover, integration of BRD9 into these complexes is critical for synovial sarcoma cells to grow."
The team developed a novel small-molecule degrader of BRD9 function and used it to target the protein. Remarkably, they found that synovial sarcoma cells are highly sensitive to the molecule, while other sarcoma subtypes are unaffected by it. When the molecule degrades BRD9 in synovial sarcoma, it subsequently inhibits tumour progression.
"We've highlighted BRD9 as the first actionable therapeutic target in synovial sarcoma tumours that is linked both biochemically and functionally to SS18-SSX," concludes senior author Scott Armstrong, Chairman of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute. "Our work paves the way for future investigation into how BRD9 degradation could be exploited for developing novel treatments against the disease."
The paper 'Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma' can be freely accessed online at https://doi.org/10.7554/eLife.41305. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.
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