We and others have demonstrated the role of gastrin releasing peptides (GRP) as an autocrine growth factor and the weight of this evidence is consistent with GRP playing an important role in early cancer formation. We have evaluated the use of a neutralizing monoclonal antibody to block the effect of this growth factor in patients with advanced small cell lung cancer. This treatment is associated with no demonstrable toxicity, but only one patient had a significant anti-tumor response. Based on this experience, we proposed to evaluate a new class of GRP antagonists that are synthetic peptides. This class of molecules may have better properties such as bioavailability and affinity than monoclonal antibodies. These molecules might also be tagged with a radioisotope to permit exact pharmacologic analysis. Synthetic peptide growth factor antagonists may be very useful for delivery as intervention agents, and we proposed to evaluate that possibility. This effort would be a model for the type of rational intervention agent research that the BPRB staff will conduct. Several peptide antagonists have been identified by evaluating in vitro cytotoxicity with lung cancer cell lines. These same analogues have been shown to have consistent growth inhibitory effects in vivo with mouse xenografts. Prior to evaluation in humans, acute and chronic toxicology studies must be performed to evaluate for unexpected patterns of side effects. We have already devised an approach to optimal dose determination for anti-GRP monoclonal antibodies; we can extend this analysis to the peptide antagonists to determine the validity of this approach in a new system. GRP is a molecule that serves as an excellent model of a neuropeptide effector which may be important as a mediator of tumor promotion dynamics in certain epithelium; as such it comprises an attractive target for intervention research.
