MYCN Function in Neuroblastoma

MYCN 在神经母细胞瘤中的功能

• 批准号: 7522470
• 负责人: NAOHIKO IKEGAKI
• 金额: $ 33.65万
• 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/7522470
• 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; Disease regression; Elderly; Enhancers; Ephrin-B3; Exhibits; Future; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genome; 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; Polymerase Chain Reaction; Preparation; Public Health; Residual Neoplasm; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Series; Site; Specimen; Staging; Subgroup; Survival Rate; Testing; Therapeutic; Thinking; Transfection; Translational Research; Tumor stage; Xenograft Model; Xenograft procedure; age group; age related; base; chemotherapeutic agent; clinically relevant; cohort; demethylation; drug efficacy; inhibitor/antagonist; insight; outcome forecast; phosphoinositide-dependent kinase 1; pre-clinical; prognostic; promoter; research study; size; 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）是一种儿童癌症，表现出有利或不利的表型。 NB病例中有20％具有MYCN扩增，这与年龄较大，晚期疾病，快速肿瘤进展以及最严重的疾病结果密切相关。但是，MYCN表达在NB中的重要性是有争议的。我们最近证明，基于MYCN的表达，MYCN扩增和患者存活，可以将NB分为三个亚组。第1组包括具有MYCN扩增和最严重疾病结果的人。第2组和第3组是NB，缺乏MYCN扩增，分别表达了低水平的MYCN表达。不过，有趣的是，第3组的存活率比第2组的存活率更好。由于通过转染的NB细胞系中MYCN的强制表达（源自第2组），因此诱发了凋亡和增强的NB基因表达。基于这些观察结果，我们假设高MYCN表达在NB中赋予了NB中相反的生物学后果，具体取决于MYCN是否被放大。此外，MYCN结合位点上依赖年龄的DNA甲基化会影响MYCN调节NB的行为。可以分别降低或增强MYCN放大或MYCN-非扩增NB中MYCN表达的化学治疗剂将对针对这些恶性肿瘤的治疗策略产生重大影响。具体而言，（目的1）我们将在MYCN表达，肿瘤阶段，患者年龄，MYCN扩增，1P和11Q缺失状态以及通过多变量Cox Recressions的大型NB组中进行良好的NB基因表达进行全面的临床相关性研究，并检查MyCn Mime-Mycn Mycn Nonnon-Nonnon-Nonnon-Nonnonnonnonnonnonnonnonnonnonnonnonnonnon-Nonnonnonnonnon nonnon-Nonnonnonnonnonnon nonnonnon nonnon nonnonnonnon nonnon nonnonnon nonnonnon nonnon nonnonnn nnn nonnn nnn nonnn nb s a。 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转移异种移植模型。公共卫生相关性：将通过调节其内在生物学来控制抵抗性恶性NB细胞的未来进步。我们预计，这一系列的翻译研究实验将确认MYCN表达如何调节此类NB细胞的恶性肿瘤的重要性。此外，我们的实验结果将有望早日引入有利的NB基因增强子和MyCN止动子中的临床试验，例如控制最小残留疾病。