MYCN Function in Neuroblastoma

MYCN 在神经母细胞瘤中的功能

• 批准号: 7686257
• 负责人: NAOHIKO IKEGAKI
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686257
• 关键词: 11q; Address; Affect; Age; Age Factors; Apoptosis; Behavior; Binding Sites; Bioinformatics; Biological; Biological Assay; Biology; Boxing; CD44 gene; Candidate Disease Gene; Cell Line; Cells; Child; Clinical; Clinical Trials; Collaborations; Correlative Study; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; DNA-Directed DNA Polymerase; Deoxycytidine; Dexamethasone; Diagnostic Neoplasm Staging; Disease; Disease Outcome; Elderly; Enhancers; Ephrin-B3; Exhibits; Future; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Global Change; Growth; Human; In Vitro; MYCN gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Methyl-CpG-Binding Protein 2; Methylation; Modeling; Molecular Profiling; Mus; N-Myc Protein; Neuroblastoma; Outcome; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pharmaceutical Preparations; Phenotype; Philadelphia; Preparation; Residual Neoplasm; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Series; Site; Specimen; Staging; Subgroup; Survival Rate; Testing; Therapeutic; Transfection; Translational Research; Tumor stage; Xenograft Model; Xenograft procedure; age group; age related; base; chemotherapeutic agent; clinically relevant; cohort; demethylation; drug efficacy; genome-wide; high risk; inhibitor/antagonist; insight; outcome forecast; phosphoinositide-dependent kinase 1; pre-clinical; preclinical efficacy; prognostic; promoter; public health relevance; research study; subcutaneous; tumor; tumor progression

DESCRIPTION (provided by applicant): Neuroblastoma (NB) is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Twenty percent of NB cases have MYCN amplification, which is strongly associated with older age, advanced stage disease, rapid tumor progression, and the worst disease outcome. However, the significance of MYCN expression in NB has been controversial. We recently demonstrated that NB can be divided into three subgroups based on MYCN expression, MYCN amplification, and patient survival. Group 1 includes those with MYCN amplification and the worst disease outcome. Group 2 and Group 3 are NB lacking MYCN amplification expressing low and high levels of MYCN expression, respectively. Interestingly though, the survival rate of Group 3 is better than that of Group 2. With the forced expression of MYCN in NB cell lines (derived from Group 2) by transfection, there is induced apoptosis and enhanced expression of favorable NB genes. Based on these observations, we hypothesize that high MYCN expression confers the opposite biological consequence in NB depending on whether or not MYCN is amplified. In addition, age-dependent DNA methylation on MYCN binding sites influences how MYCN modulates the behavior of NB. Chemotherapeutic agents that can reduce or enhance MYCN expression in MYCN-amplified or MYCN-non-amplified NB, respectively, would have great impact on therapeutic strategies against these malignant tumors. Specifically, (Aim 1) we will perform comprehensive clinical correlative studies among MYCN expression, tumor stage, patient age, MYCN amplification, 1p and 11q deletion status, and favorable NB gene expression in a large NB cohort by multivariable Cox regression models, and examine the prognostic significance of MYCN expression in subsets of high-risk MYCN-non-amplified NB by Kaplan-Meier analysis and log rank test, (Aim 2) identify MYCN target genes that provide NB with a favorable phenotype (favorable NB gene candidates) by genome wide gene expression profiling and ChIP-on-chip assay, and examine their clinical relevance in NB, (Aim 3) correlate age-dependent DNA methylation patterns and gene expression profiles in four age-based subsets (0- 6, 6-12, 12-18, and >18 months) to gain insight into the "Age Factor" of NB: the younger the patients, the better the outcome, and (Aim 4) examine the efficacy of dexamethasone, a site-specific DNA demethylation inducer in combination with DNA methylation inhibitors (5-Aza-2'- deoxycytidine and RG108) and RAS pathway specific MYCN protein destabilizers in preclinical human NB subcutaneous and metastatic xenograft models. PUBLIC HEALTH RELEVANCE: Future advances in the control of resistant malignant NB cells will be made through modulation of their intrinsic biology. We expect this series of translational research experiments will confirm the critical importance of how MYCN expression could modulate the malignancy of such NB cells. In addition, the results of our experiments will hold promise for the early introduction of favorable NB gene enhancers and MYCN-destabilizers into clinical trials, for example, in the control of minimal residual disease.

描述（由申请人提供）：神经母细胞瘤（NB）是一种表现出有利或不利表型的儿童癌症。 20% 的 NB 病例有 MYCN 扩增，这与年龄较大、疾病晚期、肿瘤快速进展和最差的疾病结果密切相关。然而，MYCN在NB中表达的意义一直存在争议。我们最近证明，根据 MYCN 表达、MYCN 扩增和患者生存情况，NB 可以分为三个亚组。第 1 组包括 MYCN 扩增且疾病结果最差的患者。第2组和第3组是缺乏MYCN扩增的NB，分别表达低水平和高水平的MYCN表达。但有趣的是，第3组的存活率优于第2组。通过转染在NB细胞系（源自第2组）中强制表达MYCN，诱导细胞凋亡并增强有利的NB基因的表达。基于这些观察结果，我们假设 MYCN 的高表达会在 NB 中产生相反的生物学结果，具体取决于 MYCN 是否被扩增。此外，MYCN 结合位点上年龄依赖性 DNA 甲基化影响 MYCN 如何调节 NB 的行为。能够分别降低或增强 MYCN 扩增或 MYCN 非扩增 NB 中 MYCN 表达的化疗药物将对这些恶性肿瘤的治疗策略产生巨大影响。具体来说，（目标 1）我们将通过多变量 Cox 回归模型对大型 NB 队列中的 MYCN 表达、肿瘤分期、患者年龄、MYCN 扩增、1p 和 11q 缺失状态以及有利的 NB 基因表达进行全面的临床相关性研究，并检查通过 Kaplan-Meier 分析和对数秩检验确定高危 MYCN 非扩增 NB 子集中 MYCN 表达的预后意义，（目标 2）确定MYCN 目标基因通过全基因组基因表达谱和 ChIP-on-chip 检测为 NB 提供有利的表型（有利的 NB 候选基因），并检查它们在 NB 中的临床相关性，（目标 3）关联年龄依赖性 DNA 甲基化模式和四个基于年龄的子集（0-6、6-12、12-18 和 >18 个月）的基因表达谱，以深入了解 NB 的“年龄因素”：患者越年轻，结果越好，并且（目标 4）检查地塞米松（一种位点特异性 DNA 去甲基化诱导剂）与 DNA 甲基化抑制剂（5-Aza-2'-脱氧胞苷和 RG108）和 RAS 途径特异性 MYCN 组合的疗效临床前人类 NB 皮下和转移性异种移植模型中的蛋白质去稳定剂。公共健康相关性：耐药性恶性 NB 细胞控制的未来进展将通过调节其内在生物学来取得。我们预计这一系列的转化研究实验将证实 MYCN 表达如何调节此类 NB 细胞的恶性程度的至关重要性。此外，我们的实验结果有望尽早将有利的 NB 基因增强剂和 MYCN 不稳定剂引入临床试验，例如控制微小残留病。