Neuroblastoma is one of the most common and most deadly neoplasms of childhood. The studies we have performed over the past 3.5 years were driven by our demonstration that nerve growth factor (NGF) imparts chemoresistance to SY5Y human neuroblastoma cells. Two cell surface receptors, TrkA and p75, have been identified for NGF. We have demonstrated that the relative abundance of p75 and TrkA on the cell surface determines whether p75-NGF contributes to neuroblastoma cell chemoresistance via independent signal transduction or via enhancement of signal transduction through TrkA. We now propose to study the determinants of TrkA-mediated effects on chemotherapeutic agent-induced apoptosis in neural crest tumor cells. We have recently found that overexpression of trkA in some neural crest tumor cells converts the function of TrkA-NGF from anti-apoptotic to pro-apoptotic, and alters the specific pathway through which TrkA-NGF signals. Over the next five years, we propose to extend and use these studies to design approaches that thwart NGF-mediated chemoresistance in neural crest tumors. We hypothesize that (1) TrkA """"""""dose"""""""" determines TrkA-NGF signaling pathway in a cell line-specific manner; (2) the specific signaling pathway triggered by TrkA phosphorylation predicts the function (i.e., pro- or anti-apoptotic) of TrkA-NGF; (3) the in vitro function of TrkA-NGF predicts its function in tumors established from murine xenografts of the same cell line; and (4) combining information regarding TrkA/p75 ratio and TrkA-NGF function facilitates prediction of the antitumor and anti-chemotherapeutic resistance efficacy of NGF receptor agonists and antagonists in vivo. We will test these hypotheses in a series of six sequential specific aims that use in vitro mechanistic information to develop strategies for in vivo approaches to the chemoresistance of neural crest tumors like neuroblastoma, and then test the efficacy of these strategies in our human tumor xenograft model system.
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