Medulloblastoma is the most common malignant brain tumor in childhood, and it ranks among the leading causes of cancer-related death in this age group. Aggressive treatment combining surgery and chemo- radiation has significantly reduced mortality rates, yet survivors frequently encounter permanent side effects and a high risk of recurrence. Dysregulation of c-Myc through somatic mutation, chromosomal translocation, genomic amplification, or defects in upstream regulators plays a significant role in human cancer development, and medulloblastoma patients with c-Myc overexpression have the worst outcome. Despite having been recognized as a major oncogene for nearly forty years, c-Myc has not been successfully targeted in cancer therapeutics. The overall objective of this project is to apply the knowledge of c-Myc suppression by microRNAs to identify novel compounds, including FDA-approved drugs that modulate the expression of these microRNAs, for medulloblastoma therapy. MicroRNAs are a class of small noncoding RNAs that negatively regulate gene expression. Data from our laboratory and others have shown that multiple microRNAs suppress the human c-Myc gene; among them, the miR-33 family (miR-33a and miR-33b) is upregulated by lovastatin and metformin, two generic drugs with sterling safety records. Building on these findings, we propose three specific aims to unravel the mechanisms of miR-33:c-Myc regulation and tumor attenuation by lovastatin and metformin and to discover novel drug candidates for miR-33-targeted therapy.
In Aim 1, we will dissect the underlying mechanisms of miR-33 upregulation in medulloblastoma cells by lovastatin and metformin.
In Aim 2, we will determine whether there is a synergistic effect of lovastatin and metformin on medulloblastoma xenograft tumor growth and metastasis through regulation of miR-33 and c-Myc.
In Aim 3, using a novel nanoparticle-based RNA detection method, we will screen 100,000 compounds to identify candidates that modulate the expression of miR-33 and subsequently reduce the expression and oncogenic action of c-Myc in medulloblastoma cells.

Public Health Relevance

The proposed research plan will provide a better understanding of the interaction between microRNAs and the c-Myc pathway in medulloblastoma. By using small molecules to modulate the expression of microRNAs and c-Myc, our findings will provide novel drug candidates to treat medulloblastoma and other cancers with c-Myc overexpression. In addition, these studies will uncover the molecular mechanisms by which statins and metformin protect patients from cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177810-01A1
Application #
8814649
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2015-04-08
Project End
2020-03-31
Budget Start
2015-04-08
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$383,141
Indirect Cost
$130,601
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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