SUMOylation Disruption Is Toxic for SS18-SSX-Driven Synovial Sarcoma
Abstract
This research addresses the Rare Cancer Research Program Fiscal Year 2022 Focus Area Therapy, to identify novel therapeutic strategies, including drug repurposing. The rare cancer this research is studying is synovial sarcoma (SS), and if this research if funded, it will help SS patients. SS is a rare sarcoma but one that is often deadly. There is one main and unique event that leads to formation of SS. This event is the abnormal formation of a protein that is referred to as SS18-SSX. Indeed, SS18-SSX is the only reoccurring mutation (genetic problem) in SS. SS normally metastasizes, resulting in a 15-year overall survival rate of less than 50%. This presents a particular problem as one-third of the patients that are diagnosed are under the age of 30. Chemotherapy has a modest and variable effect on SS patients, and immunotherapy activity is not effective. Thus, SS requires entirely new therapeutic approaches. In light of this, we tried to identify potential novel therapies. Through these collective efforts in the laboratory and through analysis of available data, we have identified a new therapeutic vulnerability in SS, namely disruption of a process termed SUMOylation. We find SS18-SSX turns on SUMOylation; and that the in-clinic SUMOylation inhibitor, TAK-981, disrupts SS18-SSX function and causes DNA damage and cell death. Excitingly, in animal models of SS, this drug causes shrinkage of SS tumors. Moreover, we found TAK-981 can combine with traditional chemotherapy used to treat SS to be even more effective. We therefore believe we have identified an important new function of SS18-SSX in SS that has immediate clinical value. This new drug therapy with the in-clinic TAK-981 can be tested in SS patients alone or with standard chemotherapy. While there are always risks of drugs not working in patients like they do in laboratory studies, or being too toxic, importantly, TAK-981 has demonstrated safety in ongoing clinical trials in other cancers (including in other combination therapies). This research will continue to build the preclinical data supporting the translation of this strategy into SS patients. Our clinical collaborator, Dr. Boikos, is co-leader of the Sarcoma Working Group at MedStar Health s Lombardi Comprehensive Cancer Center, where we would like to get this treatment into patients within the next four years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311017
Entities
People
- Anthony Faber
Organizations
- United States Army
- Virginia Commonwealth University