Molecular Therapeutics of Neuroblastoma

神经母细胞瘤的分子治疗

• 批准号: 6869553
• 负责人: XAO X TANG
• 金额: $ 24.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869553
• 关键词: DNA methylation; SCID mouse; amidohydrolases; angiogenesis inhibitors; antineoplastics; athymic mouse; carcinogenesis inhibitor; cell differentiation; cell line; clinical research; drug design /synthesis /production; enzyme inhibitors; gene expression; growth inhibitors; human tissue; neoplasm /cancer genetics; neuroblastoma; tissue /cell culture

DESCRIPTION (provided by applicant): Neuroblastoma (NB) is a common pediatric tumor, which exhibits a wide range of clinical heterogeneity. NB can regress in some cases (favorable NB) or progress relentlessly in others despite the most intensive treatment (unfavorable NB). The goal of this study is to explore therapeutic strategies for unfavorable NB based on our understanding of "Favorable NB Genes". Favorable NB genes are defined as genes whose high-level expression predicts good disease outcome of NB and forced expression of these genes in unfavorable NB results in growth suppression. Our recent studies have shown that inhibitors of DNA methylation, histone deacetylation and proteasomes reactivate favorable NB genes in unfavorable NB cells and suppress their growth in vitro and in vivo. Based on these observations, we hypothesize that chemotherapeutic agents that enhance the expression of favorable NB genes in unfavorable NB can convert these malignant tumors to the benign counterparts. To address this, (1) we will examine whether a specific histone deacetylase inhibitor, Trichostatin A (TSA) works independently or in combination with a potent proteasome inhibitor, YU101 and/or with a DNA methylation inhibitor, 5-aza-2'-deoxycitidine (5AdC), in enhancing favorable NB gene expression, inducing differentiation, and inhibiting growth and metastasis of unfavorable NB. (2) We will identify genes that provide NB with a favorable phenotype by performing gene expression profiling analyses on favorable vs. unfavorable NB and on TSA, YU101 or 5AdC-treated vs. control NB cells. We will examine the expression pattern of these favorable NB candidate genes in a cohort of NB to determine whether their high-level expression predicts favorable NB outcome. We will confirm their identity as favorable NB genes by examining their ability to suppress growth of NB cell lines in vitro and in vivo. We will determine whether the growth suppressive effect of favorable NB genes is due to inhibition of cell proliferation or acceleration of cell death. We will also examine whether the identified favorable NB genes induce differentiation and/or inhibit angiogenesis. Finally, based on their molecular characteristics, we will construct a functional relationship map among the favorable NB gene products. This map will serve as a blueprint for the development of an effective therapeutic strategy for unfavorable NB in the future.

描述（由申请人提供）：神经母细胞瘤（Neuroblastoma， NB）是一种常见的儿科肿瘤，其临床表现出广泛的异质性。在某些情况下（有利的NB）， NB可能会消退，而在其他情况下，尽管进行了最强化的治疗（不利的NB）， NB仍会持续恶化。本研究的目的是基于我们对“有利NB基因”的理解，探索不利NB的治疗策略。有利NB基因被定义为高水平表达预示着NB良好的疾病结局，而在不利NB中被迫表达导致生长抑制的基因。我们最近的研究表明，DNA甲基化、组蛋白去乙酰化和蛋白酶体抑制剂可以激活不利NB细胞中的有利NB基因，并抑制其体外和体内生长。基于这些观察结果，我们假设化疗药物可以增强不利NB中有利NB基因的表达，从而将这些恶性肿瘤转化为良性肿瘤。为了解决这个问题，(1)我们将研究一种特定的组蛋白去乙酰化酶抑制剂Trichostatin a （TSA）是否单独或与一种有效的蛋白酶体抑制剂YU101和/或与一种DNA甲基化抑制剂5-aza-2'-脱氧胞苷（5AdC）联合作用，以增强有利的NB基因表达，诱导分化，并抑制不利NB的生长和转移。(2)我们将通过对有利和不利NB以及TSA、YU101或5adc处理的与对照NB细胞进行基因表达谱分析，确定为NB提供有利表型的基因。我们将研究这些有利的NB候选基因在NB队列中的表达模式，以确定它们的高水平表达是否预示着有利的NB结果。我们将通过检测它们在体外和体内抑制NB细胞系生长的能力来确认它们是有利的NB基因。我们将确定有利的NB基因的生长抑制作用是由于抑制细胞增殖还是加速细胞死亡。我们还将研究是否已鉴定的有利的NB基因诱导分化和/或抑制血管生成。最后，根据它们的分子特征，构建NB基因有利产物之间的功能关系图谱。该图谱将作为未来发展不利NB的有效治疗策略的蓝图。