Small cell lung cancer (SCLC) represents one of the 4 major types of lung cancer. SCLC is a neuroendocrine tumor which makes and secretes high levels of bombesin/gastrin releasing peptide (BN/GRP) and insulin-like growth factor I (IGF-I). BN/GRP and IGF-I bind with high affinity to cell surface receptors and stimulate the growth of SCLC cells. The underlying hypothesis of this study is that BN/GRP and IGF-I function as autocrine growth factors in SCLC. The long term objective is to define the role of growth factors in lung cancer. This proposal concerns the biochemical characterization of BN/GRP and IGF-I as well as their receptors in human cell lines.
The specific aims are to: 1) characterize enzymes which regulate the posttranslational processing of BN/GRP. In particular, a SCLC enzyme which amidates the C-terminal of the BN/GRP will be studied. 2) The ability of somatostatin (SRIF) analogues to inhibit the secretion and biosynthesis of SCLC BN/GRP and IGF-I will be investigated.These studies will employ radioimmunoassay and molecular biology techniques. 3) BN/GRP receptors will be solubilized and purified to homogeneity from human lung cell lines. Monoclonal antibodies will be elicited against the human BN/GRP receptor and these monoclonal antibodies may serve as unique probes for the BN/GRP receptor. 4) The ability of peptide antagonists and monoclonal antibodies to inhibit the growth of SCLC will be determined. Previously, we found that certain BN analogues inhibited binding to SCLC BN/GRP receptors, the increase in cytosolic Ca 2+ caused by BN and clonal growth of SCLC cells, however, more potent BN/GRP receptor antagonists have recently been discovered. Also, the ability of anti-IGF-I receptor monoclonal antibodies to inhibit the growth of SCLC will be investigated in vitro and in vivo using nude mice. The results of these studies will provide a more comprehensive understanding about the neuroendocrine properties of SCLC and may yield new therapeutic approaches in the form of agents which inhibit the growth of SCLC.
