Molecular Therapeutics of Neuroblastoma

神经母细胞瘤的分子治疗

• 批准号: 6712870
• 负责人: XAO X TANG
• 金额: $ 5.11万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6712870
• 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）是一种常见的小儿肿瘤，表现出广泛的临床异质性。在某些情况下，NB可以在某些情况下（有利的NB）回归，或者尽管受到最密集的治疗（不利的NB），但在其他情况下可以不懈地进展。这项研究的目的是基于我们对“有利的NB基因”的理解来探索不利的NB的治疗策略。有利的NB基因被定义为基因，其高级表达预测了NB的良好疾病结果，而在不利的NB中，这些基因的强迫表达会导致生长抑制。我们最近的研究表明，对DNA甲基化，组蛋白脱乙酰化和蛋白酶体的抑制剂在不利的NB细胞中重新激活了有利的NB基因，并抑制了它们在体外和体内的生长。基于这些观察结果，我们假设增强不利NB中有利的NB基因表达的化学治疗剂可以将这些恶性肿瘤转化为良性对应物。为了解决这个问题，（1）我们将检查特定的组蛋白脱乙酰基酶抑制剂trichostatin a（TSA）是独立工作还是与有效的蛋白酶体抑制剂，YU101和/或与DNA甲基化抑制剂（5-aza-2'-二氧化氧化物的良好表达及其良好的nb）相同的蛋白酶体抑制剂（YU101）和/或结合起来NB不利的转移。 （2）我们将通过对有利与不利的NB以及TSA，YU101或5ADC处理的对照NB细胞进行基因表达分析来确定NB为NB提供有利的表型的基因。我们将在NB队列中检查这些有利的NB候选基因的表达模式，以确定其高级表达是否可以预测有利的NB结果。我们将通过检查它们在体外和体内抑制NB细胞系的生长的能力来证实其作为有利的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细胞增殖或细胞死亡加速的抑制作用。我们还将检查发现的有利的NB基因是否诱导分化和/或抑制血管生成。最后，基于它们的分子特征，我们将在有利的NB基因产物中构建功能关系图。该地图将成为开发未来不利的NB有效治疗策略的蓝图。