Targeting an RNA Binding Protein Network in Glioblastoma by Decoy RNA Oligonucleotides
Abstract
Glioblastoma (GBM) is the most aggressive brain tumor in adults with limited therapeutic options. The patient outcome is constantly poor over the past decades. Overall, among patients diagnosed with GBM in the United States between 2000 and 2014, less than half survived 1-year post- diagnosis and only 5% survived 5 years after their diagnosis. Thus, there is an urgent need for designing more effective therapeutic strategies for this fatal disease. In our research, we found widespread dysregulation of RNA alternative splicing (AS) activities in GBM, which facilitate tumor growth and could be exploited as a therapeutic target. AS is an important regulator, as the genetic information flows from DNA to RNA to proteins, by jointing the gene coding units called exons in different combinations. This allows a single gene to code for multiple protein isoforms with different, sometimes antagonized, cellular functions, thus regulating important biological processes during development, physiological processes, and diseases, including cancers. Mechanistically, AS is regulated by a group of RNA binding proteins (RBPs), which bind to a newly synthesized RNA transcript and determine the usage of exon boundaries. We previously identified that specific groups of RBPs are upregulated in GBMs and facilitate tumor progression through dictating the RNA splicing process to generate protein isoforms with oncogenic activities. However, a comprehensive investigation to describe the global changes in AS and RBPs expression in GBM has not been conducted. Moreover, whether the dysregulated AS/RBPs network could be targeted to treat GBM has also not been exploited. For these reasons, we propose to characterize the global AS and RBPs network that are dysregulated in GBM and design small RNA oligonucleotides, as a decoy-competitor, to disrupt this AS/RBPs network for GBM treatment. This project addresses two following Fiscal Year 2021 Rare Cancers Research Programs: improve our current knowledge of the biology and etiology in a rare cancer, GBM, and exploit a novel RNA- based strategy for anti-GBM therapy. The ultimate applicability of this research will help the identification of novel anti-GBM therapeutic targets to improve the overall survival rate of patients afflicted with GBM. In the past decade, RNA-based therapy has become an attractive approach for treating human diseases, including cancers. In this project, we will exploit an advanced technology with decoy RNA oligonucleotides, which is a single-strand sense RNA that is designed to competitively bind to RBPs and disrupt specific RBP/AS network. If successful, our research will provide a proof-of- concept preclinical studies and may lead to eventual clinical trials using this novel RNA-based strategy in patient population within a 5-year timeframe. This project also represents an important advance in the field of RNA therapy and will likely influence the study of other types of cancer, eventually reducing cancer-related morbidity and improving quality of life in patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210374
Entities
People
- Xiao Song
Organizations
- Northwestern University
- United States Army