Molecular Therapeutics of Neuroblastoma

神经母细胞瘤的分子治疗

• 批准号: 6947610
• 负责人: XAO X TANG
• 金额: $ 25.15万
• 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/6947610
• 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（NB）是一种常见的儿科肿瘤，表现出广泛的临床异质性。在某些情况下，NB 可能会消退（有利的 NB），而在其他情况下，尽管进行了最强化的治疗，NB 仍会不断进展（不利的 NB）。本研究的目的是基于我们对“有利的NB基因”的理解，探索不利的NB的治疗策略。有利的 NB 基因被定义为高水平表达预示 NB 疾病良好结果的基因，而这些基因在不利的 NB 中强制表达会导致生长抑制。我们最近的研究表明，DNA 甲基化、组蛋白脱乙酰化和蛋白酶体的抑制剂可重新激活不利的 NB 细胞中有利的 NB 基因，并在体外和体内抑制其生长。基于这些观察，我们假设增强不利 NB 中有利 NB 基因表达的化疗药物可以将这些恶性肿瘤转化为良性肿瘤。为了解决这个问题，(1) 我们将检查特定的组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 是否独立发挥作用，还是与强效蛋白酶体抑制剂 YU101 和/或 DNA 甲基化抑制剂 5-aza-2'- 联合发挥作用。脱氧胞苷（5AdC），增强有利的NB基因表达，诱导分化，并抑制不利的NB生长和转移。 (2) 我们将通过对有利与不利的 NB 以及 TSA、YU101 或 5AdC 处理与对照 NB 细胞进行基因表达谱分析来鉴定为 NB 提供有利表型的基因。我们将检查一组 NB 中这些有利的 NB 候选基因的表达模式，以确定它们的高水平表达是否预示着有利的 NB 结果。我们将通过检查它们在体外和体内抑制 NB 细胞系生长的能力来确认它们作为有利 NB 基因的身份。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。我们还将检查所鉴定的有利 NB 基因是否诱导分化和/或抑制血管生成。最后，根据它们的分子特征，我们将构建有利的NB基因产物之间的功能关系图谱。该图谱将作为未来针对不良 NB 制定有效治疗策略的蓝图。