The objective of this project is to identify the signal transduction pathways which control growth versus apoptosis of lung cancer cells. This information will be used to develop new therapeutic strategies for the prevention and treatment of lung cancer. A focus is given to lung cancers having neuroendocrine properties characteristic of small cell lung carcinoma. Lung cancers having neuroendocrine properties generally express neuropeptides such as gastrin releasing peptide (GRP) and the receptors for neuropeptides. The neuropeptide receptors are seven transmembrane receptors coupled to heterotrimic G proteins generally of the Gq,11 and G12, 13 family. Neuropeptide autocrine and paracrine stimulation of lung cancers having neuroendocrine features stimulate cell growth and proliferation. Studies during the past three years have demonstrated that disruption of neuropeptide autocrine/paracrine signal transduction induces apoptosis, a programmed cell death response of lung cancer cells having neuroendocrine features. Both pharmacologic and genetic disruption of neuropeptide autocrine/paracrine signaling induces apoptosis o small cell lung carcinoma cells. Dissection of signal transduction pathways in small cell lung carcinoma and other cell types indicates that a sequential protein kinase pathway involving the serine/threonine protein kinase referred to as MEK kinase (MEK) regulates apoptosis. This discovery is being used to develop gene therapy strategies for selective expression of activated MEK kinase genes and induciton of apoptosis of lung cancer cells having neuroendocrine properties. In addition, pharmacological strategies are being developed using antagonist peptides that allosterically alter the signaling of neuropeptide receptors to convert a growth stimulatory response to an apoptotic response. The antagonist peptides induce apoptosis by inhibiting specific growth stimulatory responses and activating specific MEK kinase pathways. These studies will be performed with lung cancer cells in culture and also in nude mouse tumor models. In collaboration with other project investigators of the SPORE signal transduction pathways regulating apoptosis of primary human dysplastic lung cells will be defined. Genetic and pharmacological induction of apoptosis will be characterized for lung cell dysplasias. Cumulatively, the in vitro studies to define mechanism and in vivo studies in animals will allow us to design protocols to induce apoptosis of lung cancer cells. Ultimately, these studies will be developed to a point that they can enter human clinical trials
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