Investigation of RNA m6A Demethylase Inhibition as a Novel Treatment for Glioma
Abstract
The goal of this proposal will be to increase our understanding of the epitranscriptomic landscape of gliomas. Gliomas represent the most common type of brain cancer in adults. Epitranscriptomics refers to modification of RNA transcripts, and appear to provide yet another way that cancer cells rewire the normal cellular circuitry. Our proposal will provide key insight into glioma growth and establish the feasibility of RNA demethylase inhibition for glioma therapy. This proposal addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Brain Cancer and addresses the FY19 PRCRP Military Relevance Focus Area of “Gaps in cancer prevention, early detection/diagnosis, prognosis, 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.” With an annual incidence of approximately 20,000 people in the United States, diffuse gliomas, including glioblastoma, constitute the most common primary brain cancer in adults and remain incurable for the vast majority of patients. This type of brain cancer is particularly problematic for the United States military/Veteran population based on epidemiological linkage to toxic environmental exposures among Gulf War personnel, as well as the demonstration of poorer outcomes for patients treated through the Veterans Administration Health System compared to the general population. Despite recent advances in treatment and molecular understanding of gliomas, outcomes for patients diagnosed with diffuse gliomas have not improved significantly. One of the most important reasons for this failure has been the lack of effective therapies. To address this area of unmet need, we will pursue a novel therapeutic approach. The discovery of the IDH1 mutation in gliomas in 2008 has led to a molecularly defined glioma classification system consisting of two major subtypes based on the presence or absence of the IDH1 mutation. The IDH mutation appears to be an early mutation triggering the formation of the IDH1MUT subset of gliomas through a mechanism involving generation of the oncometabolite, D-2-hydroxyglutarate (D-2- HG). D-2-HG has been shown to influence epitranscriptomics through inhibition of a key enzyme regulating this pathway. Overall, this proposal is innovative in the focus on epitranscriptomics (m6A RNA methylation) in terms of novel methodology, understanding the role of D-2-HG in glioma progression, and developing drugs targeting epitranscriptomics for glioma therapy. Several candidates are Food and Drug Administration-approved for other indications raising the potential for rapid translation to the bedside. The overall goal will be to lay the foundation for clinical trials feasible in the near future in which drugs targeting epitranscriptomics are utilized alone or in combination with existing treatments for gliomas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010457
Entities
People
- Albert Lai
Organizations
- United States Army
- University of California, Los Angeles