Neuropeptides, including mammalian bombesin-like peptides gastrin and cholecystokinin, are a structurally diverse group of molecular messengers that function in a rich network of intercellular of intercellular communication. These signaling peptides have been identified in our laboratory as potent cellular growth factors. Neuropeptides and their receptors are a major driving force behind one of the most clinically aggressive cancers, small cell lung cancer (SCLC). Our central hypothesis is that the surface receptors and the intracellular signaling pathways that mediate the proliferative and migratory responses induced by neuropeptides are potential targets for novel therapeutic interventions. Given the pivotal role of the protein kinase C (PKC) family in neuropeptide signal transduction, the studies proposed under specific aim 1 will focus on the novel PKC/PKD phosphorylation cascade in SCLC cells. Antagonists capable of blocking the biological effects of structurally unrelated neuropeptides (e.g., broad-spectrum neuropeptide antagonists) either at receptor or post-receptor levels could provide a novel approach to the treatment of SCLC and other human cancers in which multiple neuropeptides are involved as growth factors. Substance P (SP) analogues have been found in our laboratory to inhibit signal transduction and cell proliferation induced by multiple neuropeptides. These broad-spectrum neuropeptide antagonists also inhibit the proliferation of SCLC cell lines in culture, the growth of SCLC xenografts in nude mice and have entered a phase I clinical trial. As broad-spectrum neuropeptide antagonists could provide a novel approach to the treatment of SCLC and solid cancers, it is of critical importance to understand their mechanism of action. The studies proposed under specific aims 2-4 will characterize the molecular mechanism(s) by which SP analogues inhibit the binding and action of different neuropeptides.
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