For the past several years, our laboratory has been involved in the design and preclinical development of specifically targeted chemotherapeutic approaches to neuroblastoma. In the course of this work and recent work of other laboratories, it has become clear that resistance of neuroblastoma to chemotherapy correlates with the expression of tumor cell receptors for neurotrophins like nerve growth factor (NGF). Specifically, NGF can protect neuroblastoma cells from apoptosis induced by a variety of mechanically distinct chemotherapeutic agents. Two cell surface receptors have been identified for NGF. TrkA binds NGF with high affinity, while p75 binds this peptide with low affinity. Recent circumstantial evidence from several laboratories, including our own, has led to the hypothesis that the role of each of the receptors in the anti-apoptotic (and therefore chemoresistive) effect of NGF is critically dependent on the ratio of p75 to TrkA on the neuroblastoma cell surface. Preliminary data from other laboratories indicates that the p75/TrkA ratio correlates with clinical failure of chemotherapy. Using human neuroblastoma cells genetically engineered to differ only in their p75/TrkA ratio, and a series of novel highly selective p75 and TrkA ligands designed and synthesized by our co-investigator, we propose to definitively test this hypothesis both in vitro and in a nude mouse xenograft model of neuroblastoma. We will also define the downstream mechanistic changes in signal transduction that result from changes in the p75/TrkA ratio. These studies will identify therapeutic targets linked to the p75/TrkA ratio of neuroblastoma cells, and will begin to develop NGF analogues as potential therapeutic agents for overcoming NGF-mediated resistance of neuroblastoma to chemotherapeutic agent-induced apoptosis.
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