P300/CBP Inactivation: A Novel Epigenetic Therapeutic Approach for Ewing Sarcomas
Abstract
Ewing sarcoma is an aggressive cancer of the bone and soft tissues that typically occurs in children and young adults. Around 2% of all cancers in teens aged 15 to 19 are Ewing sarcoma. Despite aggressive treatment, the cancer relapses in 75% of the metastatic cases, with a 5-year survival rate of 20%. Therefore, a novel and effective therapy is greatly needed. The most common underlying genetic cause for Ewing sarcoma is EWS-FLI1, an oncogene that arose from the fusion of two genes, EWS RNA binding protein 1 (EWSR1) and Friend leukemia integration 1 (FLI1). EWS- FLI1 is a transcription factor that controls the activity of many other genes crucial for the initiation, proliferation, and metastasis of Ewing sarcoma. Transcriptional factors are considered undruggable targets, thus, a specific therapy for Ewing sarcoma based on direct inactivation of EWS-FLI1 is less likely. It was recently reported that the transcription activity of EWS-FLI1 depends on its interaction with two very similar proteins, E1A binding protein P300 (P300) and Cyclic adenosine monophosphate response element binding protein (CBP). P300/CBP are histone acetyltransferases that induce epigenetic changes to facilitate gene activation. Therefore, we hypothesized that the inactivation of P300/CBP could be an appropriate approach for suppressing EWS-FLI1 activity and an effective target for treating Ewing sarcoma. For this reason, we aim to better understand the epigenetic mechanism of EWS-FLI1/CBP/P300 axis-driven carcinogenesis and to explore P300/CBP inactivation/degradation as a targeted therapy for Ewing sarcoma. Our final goal is to develop a novel effective and specific therapy for Ewing sarcoma based on the inactivation of P300/CBP that will replace the current, in most cases, ineffective chemotherapy. Our proposal for the fiscal year 2022 Peer Reviewed Cancer Research Program addresses two Topic Areas: Cancer in children, adolescents, and young adults and Sarcoma, with the objectives of bridging the gap of an effective treatment options for Ewing sarcoma that affects military members, Veterans, their beneficiaries, and the general public alike and improving mission readiness of Service Members by minimizing patients’ time in the hospital, reducing cancer relapse, and increasing the survival rate.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310456
Entities
People
- Darko Bosnakovski
Organizations
- United States Army
- University of Minnesota