Treatment of neural tumors with either standard or experimental cancer therapies has been mostly ineffective, therefore, new approaches must be developed. The major goal of this proposed study is to identify novel targets for the development of new agents for both the prevention and treatment of neuroblastoma (NB) tumors. The availability of NB cells, which can be terminally differentiated by an elevation of the intracellular levels of cAMP, provides a unique opportunity to identify genes which may be responsible for initiating terminal differentiation in cultured NB cells. Our preliminary data show that the expression of some genes is increased, while the expression of others is decreased during cAMP-induced NB cell differentiation. Our hypothesis is that the initiation of terminal differentiation mediating by an elevation of c-AMP levels in NB cells results from increased expression of differentiation genes and decreased expression of cancer genes, and the converse change in gene expression may be needed for the initiation and maintenance of the cancer phenotype. To test this hypothesis, we propose the following specific aims: (1) to identify candidate genes that are involved in c-AMP-induced NB cell differentiation, as well as in the maintenance of a cancer phenotype; (2) to test the ability of the candidate differentiation genes, whose expression is up-regulated during c-AMP- induced differentiation, to independently induce differentiation in NB cells, when their expression is experimentally elevated; (3) to test the ability of the cancer genes whose expression is down regulated during c-AMP-induced differentiation to independently induce differentiation in NB cells when their expression is experimentally reduced; (4) to determine whether or not the simultaneous up-regulation of a differentiation gene and down-regulation of a cancer gene induces NB cell differentiation: and (5) to determine the effect of c-AMP on differentiation in subclones of NB cells which either have elevated expression levels of a candidate differentiation gene or decreased expression levels of a cancer gene, or both. We have the experience with all the proposed techniques. Future studies will focus on the regulatory mechanisms for each of the differentiation and cancer genes.
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