Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Despite the most advanced treatment with combinations of surgery, radiotherapy and chemotherapy, GBM is associated with a median life expectancy of only ~15 months. Targeted molecular therapies are arguably one of the most promising approaches to achieving more effective future GBM therapies. A major challenge facing such an approach is the simultaneous deregulation of multiple molecules in any given single tumor, as demonstrated by The Cancer Genome Atlas (TCGA) and other published research. Because of this co-deregulation, it is not surprising that molecular monotherapies have failed to achieve significant improvements in GBM clinical outcomes. Several lines of evidence suggest that the simultaneous targeting of multiple deregulated molecules and pathways is required to achieve better therapies. Based on preliminary evidence, we hypothesize that there exist ?master regulatory microRNAs? (miRNAs) that simultaneously regulate multiple deregulated molecules in GBM. The goal of this application is to discover, investigate, and therapeutically exploit such miRNAs. We believe that studying them will provide new information on the mechanisms of gene expression (de)regulation in GBM and that restoring or inhibiting them can be exploited for therapy. We propose three specific aims.
In aim 1, we will use a novel screening approach, PAR-CLIP, in combination with smRNA-seq and TCGA gene expression data analysis to uncover global miRNA targets and identify single miRNAs (designated master regulatory miRNAs) that simultaneously target and regulate the largest number of deregulated molecules in GBM.
In aim 2, we will investigate the functions and modes of action of these master regulatory miRNAs and validate their expressions and targets in human GBM specimens.
In aim 3, we will test miRNAs as novel experimental therapeutic agents or targets in GBM. Thereby, we will develop and use novel potentially clinically applicable local and systemic delivery agents and approaches including brain penetrating nanoparticles (BPN), convection-enhanced delivery (CED) and focused ultrasound with microbubbles (FUS-MB). Successful completion of the proposed studies would establish the first compendium of miRNA targets in GBM, generate new knowledge on the (de)regulation of gene expression by miRNAs and their effects on GBM malignancy, and develop novel technologies for the exploitation of novel master regulatory miRNAs in GBM therapy.

Public Health Relevance

Glioblastoma is the most common malignant brain tumor and one of the deadliest human cancers. One of the most promising approaches for glioblastoma therapy is the targeting of deregulated molecules that drive tumor malignancy. However, it has been shown that several molecules are simultaneously deregulated in any given single tumor. Targeting them altogether with pharmacological drugs is extremely difficult because many molecules have no known drugs and because combining several drugs leads to high toxicity. To overcome this problem, we propose to use a new class of naturally occurring nucleic acids called microRNAs that can target several molecules at the same time. We propose to identify such molecules, study their mechanisms of action and effects, and test them as new experimental therapeutic drugs. If successful, these studies will improve our understanding of the molecular mechanisms of glioblastoma and lead to the development of new and more efficient therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA220841-03
Application #
9743754
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fingerman, Ian M
Project Start
2017-08-09
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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