Trinity scientists have developed a potential new therapeutic approach for synovial sarcoma, a common soft-tissue childhood cancer. Pre-clinical trials in mice showed that the newly developed drug blocked tumour progression. The team, led by Dr Gerard Brien of the school of genetics identified “molecular vulnerabilities” in the synovial sarcoma, according to a paper recently published in the international journal eLIFE.
The team used CRISPR-based genomic screening technologies to identify a protein BRD9, which plays a critical role in the cell growth of the tumours. In addition, the team set out to develop drugs which “degrade” the BRD9 and hence inhibit tumour progression. They confirmed through biochemical studies in synovial sarcoma cells that BRD9 partners with the disease-causing SS18-SSX protein, and thus supports it in driving cancer development.
Following this development, Dr Brien and his team have created a new BRD9 “degrader” drug. Pre-clinical trials in mice showed that the drug was highly selective and was successful in blocking the progression of synovial sarcoma tumours. The synovial sarcoma cells were found to be highly sensitive to the degraders, while other sarcoma cells were unaffected. The next step will be clinical trials in patients, which the scientists are hoping will take place in the near future.
Commenting on the breakthrough, Dr Brien said: “As the term degrader suggests, the drug we created “degrades” the BRD9 protein, removing it from cancer cells. It essentially ‘tricks’ the cells into eliminating this protein on which they rely, which in turn leads to their death.”
“Excitingly, our work demonstrates that degrading BRD9 impedes the SS18-SSX protein, which is the underlying cause of synovial sarcoma. We also found that our new drug primarily impacts cellular processes important in synovial sarcoma, but not normal cells. This is very important, because it should result in less unwanted side-effects in patients. We now hope these promising findings will lead to clinical trials of this new drug in patients in the near future.”
Synovial sarcoma is one of the most common soft-tissue cancers in teenagers and adults, and long-term survival rates for patients of this cancer stand at below 50%. Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which is caused by a genetic mutation and responsible for the development of the disease. Targeting the SS18-SSX protein has long been considered as an ideal method to hindering the progression of synovial sarcoma, however, this protein was found to be largely unmanageable using therapeutic intervention.
Clustered regularly interspaced short palindromic repeats (CRISPR) is a genome editing tool used to modify human genomes which contain errors or mutations. CRISPR is a naturally-occurring system used by bacteria to ‘cut up’ the DNA of invading bacterial viruses for immune defense. Today, this technology is harnessed by scientists for editing genes. By cutting a cell’s genome at a desired location, genes can be removed from the genome, or new cells can be added. This method can be used to correct errors in genomes which are causing life threatening diseases.