BOMBESIN-LIKE PEPTIDE RECEPTORS AND HUMAN LUNG CANCER

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The autocrine growth system for bombesin-like peptides (BLP) in human small cell lung carcinoma (SCLC) has generated much interest as one growth factor receptor system which may have clinical utility. Originally thought to involve gastrin releasing peptide (GRP, mammalian bombesin) and its receptor, evidence is now emerging that abnormal expression of one or more related receptors, including a previously uncharacterized BLP receptor, contributes to the malignant growth of human SCLC. The hypothesis to be tested is that BLP receptors are overexpressed in human SCLC, pulmonary dysplasia and in some smokers. This overexpression contributes to the proliferative advantage of malignant or premalignant cells and can be exploited to improve patient management via diagnostic, prognostic and/or therapeutic maneuvers. The overall goal of this proposal is to exploit preclinical studies of BLP receptors to further develop and apply tools to determine whether BLP receptors can be utilized to improve management of patients with lung cancer. The unique collaborative opportunities provided by the SPORE will expedite the success of this endeavor. The specific aims of this project are: 1) Determination of the distribution of various BLP receptors in normal human lung and human lung cancer using in situ hybridization to identify cells expressing receptor mRNA and immunocytochemistry with highly specific antibodies to identify cells expressing receptor proteins; 2) Assessment of whether changes in human pulmonary BLP receptor expression: a) occur in smokers compared with nonsmokers, b) precede or accompany development of pulmonary dysplasia, c) predict SCLC patient outcome, and d) occur after smoking cessation and/or chemoprevention; 3) Identification and cloning of novel BLP receptors in human SCLC using degenerate oligonucleotide primers derived from very homologous sequences in the GRP and neuromedin b receptors and PCR as has been used to clone other new members of the family of seven membrane- spanning domain receptors; 4) Investigation of the utility of BLP receptors as potential targets for SCLC tumor imaging and/or treatment using human tumor xenografts in nude mice.