Targeting Bmi1 for ATRT Therapy
Abstract
This proposal addresses the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Pediatric Brain Tumors and the FY21 PRCRP Military Health Focus: Mission Readiness. Addressing gaps in prognosis, and/or treatment 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. Atypical teratoid rhabdoid tumors (ATRT) are highly malignant brain tumors of childhood. Current therapy consisting of chemotherapy and radiation is infective and highly toxic with a 40% survival rate and significant long-term side effects that impact child and family function. ATRT are driven by mutations or deletions of a gene called SMARCB1. This results in abnormal regulation of how genes are packaged in DNA and thus turned on or off. We postulated that other genes that also regulate DNA packaging may co- operate with SMARCB1 loss to drive ATRT. To identify these interacting genes which may be new therapeutic targets in ATRT we performed a gene knockdown study targeting over 400 genes. We found that BMI1 was a critical gene that co-operates with SMARCB1 loss to drive ATRT. How BMI1 functions in ATRT is not known. Furhter recent new inhibitors of BMI1 have been developed and may have potential as new agents for ATRT therapy. In this proposal we will investigate the role of BMI1, in regulating ATRT tumor growth and the potential for targeting this gene with new inhibitors. The proposed research is relevant to the Department of Defense’s mission, because discovery and validation of new targets for therapy of pediatric brain tumors will improve the treatment of such tumors while minimizing toxic effects of current therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210946
Entities
People
- Rajeev Vibhakar
Organizations
- United States Army
- University of Colorado Denver