Modulation of MicroRNAs with Xenobiotics to Target c-Myc

用异生素调节 MicroRNA 以靶向 c-Myc

基本信息

批准号：
10018536
负责人：
Yong Li
金额：
$ 27.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018536
关键词：
3&apos Untranslated Regions Animals Antineoplastic Agents Attenuated Binding Biogenesis Blood - brain barrier anatomy Brain Brain Neoplasms Cancer Etiology Cancer Intervention Cancer Patient Cells Cessation of life Childhood Cholesterol Chromosomal translocation Combined Modality Therapy Data Defect Detection Development Diabetes Mellitus Dose Expression Profiling FDA approved Family Gene Expression Generic Drugs Genes Genetic Transcription Genomics Human Human Genome Hyperglycemia Introns Knowledge Laboratories Lovastatin MYC gene Malignant Neoplasms Malignant neoplasm of brain Messenger RNA Metabolism Metformin Methods MicroRNAs Molecular Molecular Genetics Mus Neoplasm Metastasis Nucleotides Oligonucleotides Oncogenes Oncogenic Oncoproteins Operative Surgical Procedures Outcome Pathway interactions Patients Pharmaceutical Preparations Play Preventive therapy Primitive Neuroectodermal Tumor RNA RNASE3L gene Records Recurrence Regulation Reporter Research Role Safety Small RNA Somatic Mutation Specimen Survivors Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transcript Treatment Efficacy Tumor Cell Line Untranslated RNA Up-Regulation Work Xenobiotics Xenograft procedure age group attenuation base c-myc Genes cancer cell chemoradiation drug candidate high risk high throughput screening hypercholesterolemia improved medulloblastoma mortality mutant nanoGold nanoparticle novel novel therapeutics outcome forecast overexpression pre-clinical preference promoter public health relevance side effect small molecule targeted treatment tool transcription factor transcriptome sequencing tumor tumor growth tumor metabolism tumor xenograft tumorigenesis

项目摘要

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.

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，它在该年龄段的癌症相关死亡的主要原因之一中。相结合手术和化学辐射的积极治疗显着降低了死亡率，但幸存者经常遇到永久性副作用和重复的高风险。通过体细胞突变，染色体易位，基因组扩增或上游调节剂中的缺陷对C-MYC的失调起着重要作用人类癌症发育和C-MYC过表达的髓母细胞瘤患者的结果最差。尽管近四十年来一直被公认为是主要的癌基因，但C-MYC尚未成功针对癌症治疗剂。该项目的总体目的是应用microRNA抑制C-MYC的知识来鉴定新的化合物，包括调节这些microRNAS表达的FDA批准药物，用于髓母细胞瘤治疗。 microRNA是一类负调节基因表达的小型非编码RNA。我们实验室和其他人的数据表明，多个microRNA抑制了人类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，这是两种具有纯安全记录的通用药物。在这些发现的基础上，我们提出了三个特定的目的，旨在揭示miR-33：lovastatin和二甲双胍的MiR-33：C-MYC调节和肿瘤衰减的机制，并发现用于miR-33靶向miR-33靶向治疗的新型药物候选者。在AIM 1中，我们将通过lovastatin和二甲双胍剖析髓母细胞瘤细胞中miR-33上调的基本机制。在AIM 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异种肿瘤生长和转移的协同作用。在AIM 3中，使用一种新型的基于纳米颗粒的RNA检测方法，我们将筛选100,000种化合物，以鉴定调节miR-33表达的候选物，然后降低C-Myc在髓母细胞瘤细胞中的表达和致癌作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy.

miR-153抑制IDO1表达并增强CAR T细胞免疫治疗

DOI：
10.1186/s13045-018-0600-x
发表时间：
2018-04-23
期刊：
Journal of hematology & oncology
影响因子：
28.5
作者：
Huang Q;Xia J;Wang L;Wang X;Ma X;Deng Q;Lu Y;Kumar M;Zhou Z;Li L;Zeng Z;Young KH;Yi Q;Zhang M;Li Y
通讯作者：
Li Y

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