Molecular Therapeutics of Neuroblastoma

描述(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。尽管进行了最密集的治疗(不利的NB)，但在某些情况下，NB可以退化(有利的NB)或在其他情况下无情地进展。本研究的目的是基于我们对“有利的NB基因”的理解，探索治疗不良NB的策略。有利的NB基因被定义为其高水平的表达预示着NB良好的疾病结局，而强迫这些基因在不利的NB中表达会导致生长抑制。我们最近的研究表明，DNA甲基化、组蛋白去乙酰化和蛋白酶体的抑制剂重新激活了不利的NB细胞中的有利的NB基因，并在体外和体内抑制了它们的生长。在这些观察的基础上，我们假设化疗药物可以增强不利的NB中有利的NB基因的表达，可以将这些恶性肿瘤转化为良性对应的肿瘤。为了解决这一问题，(1)我们将研究特异组蛋白脱乙酰酶抑制剂trichostatin A(TSA)是否单独或与有效的蛋白酶体抑制剂YU101和/或DNA甲基化抑制剂5-aza-2‘-deoxcitidine(5AdC)联合作用，促进有利的NB基因表达，诱导分化，抑制不利的NB的生长和转移。(2)我们将通过对有利和不利的NB以及TSA、YU101或5AdC处理的NB细胞和对照NB细胞进行基因表达谱分析来确定为NB提供有利表型的基因。我们将检查这些有利的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了细胞的增殖还是加速了细胞的死亡。我们还将研究已确定的有利的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。这张地图将作为未来开发针对不良NB的有效治疗策略的蓝图。

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.