Synovial sarcoma is one of the most common soft tissue cancers in teenagers and young adults, and one of the most difficult to treat. Long term survival rates for synovial sarcoma patients currently sit well below 50 percent, a sobering figure given that the genetic abnormality responsible for the disease has been known to scientists for years. Every confirmed case of synovial sarcoma involves the same singular genetic mutation, present in 100 percent of patients, that produces a harmful fusion protein called SS18 SSX which drives cancer development. Despite this unusually clear biological target, no effective therapeutic approach had been developed to impede it, until now.
How Scientists Identified BRD9 as a Synovial Sarcoma Vulnerability
Researchers led by Dr. Gerard Brien, Research Fellow in Genetics at Trinity College Dublin, used CRISPR based genomic screening technology to perform systematic genetic screens across synovial sarcoma cells in search of molecular vulnerabilities. The goal was to identify proteins that synovial sarcoma tumors depend on for survival and that could therefore serve as drug targets.
The screens identified BRD9 as a protein essential to the survival of synovial sarcoma cells. Biochemical studies then confirmed that BRD9 forms a partnership with the disease causing SS18 SSX fusion protein, actively supporting its role in driving cancer development. This partnership made BRD9 an especially compelling target: disrupting it would not only remove a protein the cancer depends on directly but would simultaneously impede the underlying fusion protein responsible for the disease.
The study was published in the international journal eLife.
The BRD9 Degrader Drug and What It Does in Synovial Sarcoma Cells
Using contemporary drug design approaches, the research team developed a new BRD9 degrader compound designed to eliminate the BRD9 protein from cancer cells rather than simply inhibiting its activity. As Dr. Brien explained, the drug essentially tricks cancer cells into eliminating a protein on which they depend, which in turn leads to cell death.
In preclinical trials conducted in mouse models, BRD9 degradation successfully blocked the progression of synovial sarcoma tumors. Critically, the drug was found to primarily affect cellular processes important in synovial sarcoma rather than in normal, healthy cells. This selectivity is a significant finding because it suggests the treatment could carry a lower side effect burden than conventional chemotherapy approaches, which do not distinguish between cancerous and healthy tissue.
Why This Approach Matters for Synovial Sarcoma Patients
Synovial sarcoma patients respond poorly to conventional treatment, which is a primary reason survival rates have remained so low despite decades of research. The discovery of a druggable protein that is both essential to tumor survival and directly linked to the disease causing mutation represents a meaningful shift in the therapeutic landscape for this cancer.
The fact that SS18 SSX is present in every single synovial sarcoma case also means that a therapy targeting its BRD9 dependent mechanism could, in principle, apply broadly across the patient population rather than being limited to a molecular subtype.
Next Steps Toward Clinical Trials in Synovial Sarcoma
Following the promising preclinical results, the research team’s next step is to advance the BRD9 degrader drug into clinical trials in patients. Dr. Brien expressed hope that this transition will occur in the near future, given the strength of the preclinical data and the clear unmet need in the synovial sarcoma patient population.
For patients and families affected by synovial sarcoma, participation in early phase clinical research offers the possibility of accessing emerging therapies while contributing to the evidence base that will shape future treatment standards.
FOMAT conducts oncology clinical trials at sites across the United States. To explore active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at R&D Magazine.