A Gene Therapeutic Approach for the Treatment of Lung Cancers

Small cell lung carcinomas and many non-small cell lung carcinomas have been shown to be dependent on bombesin-like peptides as growth factors. The bombesin-like peptides are normally metabolized by the peptidase neprilysin found in the lung. Neprilysin levels decrease and bombesinlike peptide levels increase in lung cancer. Neprilysin has been shown to be inactivated by cigarette smoke, providing a link between smoking and lung cancer. In this proposal we will test the ability of recombinant neprilysin, delivered to the lungs through a lentivirus vector, as a method of treating ethyl carbamate induced adenocarcinomas in a mice. In this system we will test the ability of cell surface and secreted forms of neprilysin to hydrolyze the bombesin-like peptide growth factors leading to arrest of growth of the lung cancer. We also propose to use structural data to produce by genetic engineering a form of neprilysin that is more specific for bombesin-like peptides and use this form of the enzyme in the mouse model.