Modulation of MicroRNAs with Xenobiotics to Target c-Myc

描述(申请人提供)：髓母细胞瘤是儿童最常见的恶性脑肿瘤，是该年龄段癌症相关死亡的主要原因之一。手术和化疗相结合的积极治疗显著降低了死亡率，但幸存者经常会遇到永久性的副作用和高复发风险。C-Myc通过体细胞突变、染色体易位、基因组扩增或上游调节因子缺陷而调节失调在 人类肿瘤的发生、发展和髓母细胞瘤c-Myc过度表达的患者预后最差。尽管近40年来，c-Myc一直被认为是一种主要的癌基因，但它在癌症治疗中一直没有成功地被靶向。这个项目的总体目标是应用microRNAs抑制c-Myc的知识来识别新的化合物，包括FDA批准的调节这些microRNAs表达的药物，用于髓母细胞瘤的治疗。MicroRNAs是一类非编码的小RNA，负向调节基因表达。来自我们实验室和其他实验室的数据表明，多个microRNAs抑制人类c-Myc基因；其中miR-33家族(miR-33a和miR-33b)被洛伐他汀和二甲双胍上调，这两种仿制药具有良好的安全性记录。在这些发现的基础上，我们提出了三个特定的目标来揭示miR-33的机制：C-Myc调节和洛伐他汀和二甲双胍对肿瘤的抑制，并发现miR-33靶向治疗的新候选药物。在目标1中，我们将剖析洛伐他汀和二甲双胍上调髓母细胞瘤细胞miR-33表达的潜在机制。在目标2中，我们将通过调节miR-33和c-Myc来确定洛伐他汀和二甲双胍对髓母细胞瘤移植瘤生长和转移是否有协同作用。在目标3中，我们将使用一种新的基于纳米颗粒的RNA检测方法，筛选100,000个化合物，以确定调控miR-33表达的候选化合物，并随后降低c-Myc在髓母细胞瘤细胞中的表达和致癌作用。

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.