A Novel Strategy to Target the EWS-FLI1 Oncoprotein in Ewing Sarcoma
Abstract
This proposal addresses the Fiscal Year 2019 Peer Reviewed Cancer Research Program Topic Area “Cancer in children, adolescents, and young adults.” Ewing sarcoma (EWS) is a cancer arising in bone and soft tissue of children and young adults, and it is fatal if untreated. EWS treatments can have severe long-term side effects for survivors: accelerated coronary artery disease, heart damage, and even second cancers. Patients with metastatic EWS usually have a poor prognosis, and most unfortunately succumb to their disease. There is an urgent need for new EWS therapies, to cure patients with metastatic cancer, and to avoid the negative consequences of current treatments. EWS cells possess a unique protein called EWS-FLI1, which is made from an aberrant gene fusion that occurs in EWS. EWS-FLI1 functions by binding DNA and turning on expression of genes that are important for the cancerous properties of EWS cells. EWS cells depend on EWS-FLI1 for survival and growth. No means of directly blocking EWS-FLI1 itself has yet been identified. EWS-FLI1 is an attractive target for EWS treatment, since normal cells do not possess EWS-FLI1. Therefore, therapies directed against EWS-FLI1 would likely be effective at killing EWS cells but exert few negative effects in normal cells. Our group studies a protein called SIRT5, which removes a chemical modification called succinylation on its target proteins. We find that SIRT5 regulates succinylation on EWS-FLI1, and that this effect is important for the function of EWS-FLI1. EWS cells lacking SIRT5 rapidly die. Unravelling the details of this SIRT5/EWS-FLI1 link is the focus of our project. Importantly, normal cells and whole mice lacking SIRT5 are mostly healthy. Our work may provide an approach to kill EWS cells, with little impact on normal organs, by inhibiting SIRT5 and thereby, EWS-FLI1 function. We and others are developing new small molecules that block SIRT5 function to achieve this goal. This proposal addresses the FY19 PRCRP Military Health Focus Area “Gaps in … treatment and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.” Unfortunately, there are no published data on the incidence of EWS specifically in military Service members, Veterans, or their beneficiaries. However, the mean age of EWS onset is 15 years, and EWS occurs in both children and in young adults. Therefore, EWS would be expected to afflict the young dependents of Service personnel, as well as occasionally younger Service personnel themselves, at roughly the same rates as the general population. The prolonged, intensive regimens needed to treat EWS may pose special hardships in the context of military Service members and their dependents. Depending on the results of diagnostic and staging testing, EWS is treated with combinations of chemotherapy, radiation, and/or surgery (PDQ Cancer Information Summary, NCI, 2019). These treatments typically last 6-12 months, likely necessitating that a Service member who is a parent of a young child take Military Caregiver Leave per the Family and Medical Leave Act to tend to the sick child. Moreover, as noted above, even in patients who are cured of EWS, there can be permanent side effects of EWS treatments. These can include premature cardiac disease, an increased incidence of second cancers, and functional impairment due to orthopedic issues after surgery. Most ominously, when EWS recurs, it necessitates further intensive therapy and carries a poor prognosis. For EWS survivors who are military Service members themselves, or who care for children suffering from EWS, all of these issues are likely to seriously hamper mission readiness. Our proposal focuses on a potential improved, and less toxic treatment strategy for EWS, via targeting the EWS-FLI1 transcription factor, thus addressing these important challenges.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010614
Entities
People
- David B. Lombard
Organizations
- United States Army
- University of Michigan