Lung cancer is the leading cause of death from neoplasia in the United States. Because of the large number of aging smokers and ex-smokers in the U.S. population, the incidence of lung cancer will remain high for the next 20-30 years, despite the overall decline in smoking. Current therapies for lung cancer are inadequate; the 5-year survival rate is only about 10%, unchanged from 50 years ago. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung tumors, and is not responsive to conventional chemotherapy. Peptide growth factors that induce proliferation of lung tumor cells represent a potential avenue for therapeutic manipulation. For such a strategy to be successful, it may be necessary to intervene in several growth factor pathways. Our previous work has documented the mitogenic effects of the novel growth factors (IE1 (produced from the E domain of the Insulin-like Growth Factor IB [IGF-I] prohormone) on normal and neoplastic lung epithelial cells. We have further documented the responsiveness of normal lung epithelial cells and NSCLC cells to gastrin- releasing peptide (GRP). In this renewal application, we seek to provide further evidence for the hypothesis that IBE1 and GRP (or related neuropeptides) are important regulators of cell proliferation in NSCLC and in the bronchial mucosa. We propose to examine effects of these two peptides lone and in combination with two well-described mitogens for the lung epithelium, epidermal growth factor (EGF) and IGF-I. We will examine effects in primary and early passage cultures of human bronchial epithelial (HBE) cells and lung tumor cells.
The Specific Aims are: 91) To determine the role of the newly discovered factor IBE1 in growth of NSCLC; (2) to determine the role of GRP and related neuropeptides in growth of NSCLC; (3) to determine the effect of blocking the actions of iBE1 and GRP on cell proliferation and cell signalling, and the effect of blocking mitogens in combination.
In Aim 1, we will purify and sequence the IBE1 molecule from a lung cancer cell likne to demonstrate that it is indeed produced in lung tumors from the IGF-IB prohormone. We will also use the purified peptide to demonstrate its mitogenic activity. We further plan to cross-link the receptor for IBE1 and characterize and purify the receptor. This will be complimented by screening of an expression library to find cDNA clones encoding the receptor.
In Aim 2, we will demonstrate a mitogenic effect of GRP and the related peptide neuromedin B on lung epithelia and will demonstrate receptors for these peptides in HBE cells and NSCLCs.
In Aim 3, we will examine the ability of antibodies and/or antagonists of these two peptides to inhibit growth of NSCLC in vitro and in vivo alone or in combination with reagents that block other lung mitogens.
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