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.
