Neuroblastoma is the most common extracranial solid tumor of childhood. Some tumors regress spontaneously; others respond well to therapy and are cured; however, most respond but recur or never respond. Differences involving genes that effect tumor cell growth, survival, and differentiation probably cause this clinical diversity. Our investigations of the N-myc proto-oncogene, the high affinity receptor for nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) have defined biological subsets of neuroblastomas with clinical importance. These observations, together with fundamental discoveries about Myc proteins and neurotrophins, suggest that N-myc and neurotrophins have important roles in determining the malignant behavior of neuroblastoma. We hypothesize that BDNF promotes tumor cell survival and possibly tumor progression, whereas NGF limits growth and induces differentiation.
Our specific aims will address this hypothesis and evaluate laboratory- clinical correlations to define prognostic factors. They are as follows: l) determine if BDNF is a survival factor for neuroblastoma and if autocrine expression is associated with tumor progression; 2) determine if NGF, via its high affinity receptor (gp140trk), effects growth and differentiation and if the combination of NGF and high affinity receptor expression by tumor cells is associated with tumor regression; and 3) determine by multivariate analyses the relative importance of N-myc, neurotrophin receptors, and neurotrophins in prognostication. In laboratory-clinical studies, tumor N-myc, tumor neurotrophins and receptors, tumor histology, paracrine and serum neurotrophins, age and clinical stage, tumor regression and progression, and survival will be compared. These investigations will be performed in conjunction with therapeutic protocols of the nationwide Childrens Cancer Group in which patients receive therapy according to a clinical and laboratory risk classification. Specimens have been banked since 1980, and they continue to be obtained prospectively from approximately 80% of 200 patients enrolled in CCG protocols annually. Basic laboratory studies of BDNF, NGF, and N-myc will utilize human neuroblastoma cell lines. Tumor cell requirement for BDNF will be evaluated by transducing antisense BDNF cDNA with retroviral vectors and by developing antibodies to BDNF and its high affinity receptor, gp145trkB NGF non-responsive cell lines will be transduced with full-length trk cDNA, which encodes gp145trk, to determine if providing a functional high affinity receptor renders them NGF responsive. The generality of findings will be assessed with a panel of cell lines, including those with and without genomic amplification of N- myc, that represent the known biologic subtypes of aggressive neuroblastoma. These studies should elucidate the roles of BDNF, NGF, and N-myc in neuroblastoma regression and progression and should contribute to improved prognostication through the development of reagents and definition of prognostic factors. They also should provide a biologic basis for new therapeutic strategies.
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