Modulation of MicroRNAs with Xenobiotics to Target c-Myc

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DESCRIPTION (provided by applicant): 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.