Modulation of MicroRNAs with Xenobiotics to Target c-Myc

描述（由申请人提供）：髓母细胞瘤是儿童期最常见的恶性脑肿瘤，是该年龄组癌症相关死亡的主要原因之一。结合手术和放化疗的积极治疗显著降低了死亡率，但幸存者经常遇到永久性副作用和复发的高风险。通过体细胞突变、染色体易位、基因组扩增或上游调控因子缺陷引起的c-Myc调控异常在以下方面起重要作用： 人类癌症的发展，并且具有c-Myc过表达的髓母细胞瘤患者具有最差的结果。尽管c-Myc被认为是一种主要的致癌基因已有近40年的历史，但在癌症治疗中尚未成功靶向c-Myc。该项目的总体目标是应用microRNA抑制c-Myc的知识来鉴定新型化合物，包括FDA批准的调节这些microRNA表达的药物，用于髓母细胞瘤治疗。MicroRNA是一类负调控基因表达的非编码小RNA。来自我们实验室和其他实验室的数据表明，多种microRNA抑制人类c-Myc基因;其中，miR-33家族（miR-33 a和miR-33 b）被洛伐他汀和二甲双胍上调，这两种仿制药具有出色的安全性记录。基于这些发现，我们提出了三个具体的目标来阐明miR-33的机制：c-Myc调控和洛伐他汀和二甲双胍的肿瘤衰减，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中miR-33的潜在机制。在目标2中，我们将确定洛伐他汀和二甲双胍是否通过调节miR-33和c-Myc对髓母细胞瘤异种移植肿瘤生长和转移具有协同作用。在目标3中，使用一种新的基于纳米颗粒的RNA检测方法，我们将筛选100，000种化合物，以鉴定调节miR-33表达并随后降低成神经管细胞瘤细胞中c-Myc表达和致癌作用的候选物。

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.