Malignant brain tumors of glial origin remain today as a serious clinical and scientific problem as ever. Patients with the most malignant glioma, glioblastoma, have an average survival time of less than one year. Like other cancers, gliomas are diseases caused by dysregulated cell proliferation, differentiation, migration and death. However, molecular events that lead to dysregulation of these key processes are not well understood. How gene expression is controlled in tumor formation will be a critical issue in understanding the biology of these tumors. Recently, a novel class of small regulatory molecules, microRNA (miRNA), has been implicated in post-transcriptional regulation of gene expression in a wide range of cancers. A number of miRNAs are aberrantly expressed in gliomas, and some of them may regulate expression of important oncogenes and tumor suppressors. The overall goal of this proposal is to validate miRNAs playing a functional role in human glioma formation and to elucidate intracellular signaling pathways that mediate functions of these miRNAs. To achieve this goal, selected oncogenic miRNAs will be inhibited in glioma cells and effects of these manipulations on in vitro and in vivo parameters of glioma growth will be examined. Since miRNA inhibition may potentially produce various off-target effects, Specific Aim 1 will involve validation of highly specific oligonucleotide inhibitors for the miRNAs of interest. Using these specific tools, we will validate key mRNA targets that mediate miRNA functions in glioma cells.
In Specific Aim 2 we will determine effects of the miRNAs on glioma cell viability, proliferation, and apoptosis in vitro.
In Specific Aim 3, using ex vivo and in vivo approaches, we will further determine effects of the miRNAs and most potent miRNA combinations on growth and invasion of intracranial glioma tumors in animal models. The proposed work promises to yield significant new insights into the biology of glioma, and more generally - gene expression in cancer, and may validate a novel class of molecular targets for glioma therapy.

Public Health Relevance

Despite very aggressive treatments, survival for patients diagnosed with malignant brain tumor, glioblastoma, has only marginally changed over the past 25 years. There is a critical need for new molecular targets, concepts and approaches to treat this devastating disease. Recently discovered small regulatory RNA molecules, known as microRNAs, regulate molecular events involved in tumor formation in the brain. The proposed work on microRNAs holds promises to advance our understanding of brain tumors and may open the door to novel treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138734-04
Application #
8391230
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mietz, Judy
Project Start
2010-01-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$330,591
Indirect Cost
$141,392
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Teplyuk, Nadiya M; Mollenhauer, Brit; Gabriely, Galina et al. (2012) MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 14:689-700
Gabriely, Galina; Yi, Ming; Narayan, Ravi S et al. (2011) Human glioma growth is controlled by microRNA-10b. Cancer Res 71:3563-72