The goal of the proposed work is the development of platform targeting agents for cancer imaging and therapy. These agents are multimeric ligands directed against combinations of cell surface receptors or epitopes that will bind with higher affinity and specificity compared to their component monomers. They will have advantages over agents directed against single epitopes (e.g. antibodies, Fab) in that they will not only rely on a single overexpressed cell surface protein, and they will have relatively low M.W. (Ca. 5 kD). Two hypotheses drive this work. 1) Heteromultimeric ligands directed against combinations of receptors or epitopes will bind with higher affinity and apparent cooperativity compared to individual monomers. 2) Individual cell types can be uniquely defined by combinations of expressed cell surface proteins. These hypotheses will be pursued throughout both phases of the proposed work. Hypothesis 1 will be tested in a model system comprised of four ligand-receptor combinations with which we have experience (melanotropin (MSH), oxytocin, cholecystokinin (CCK) and enkephalins). Hypothesis 2 will be tested by screening the expression patterns of 244 cell surface proteins associated with Pancreatic Adenocarcinoma (PaAdo). The first phase of this screen will use a custom DNA array, which will generate comprehensive data sets to identify potential targets. These will be confirmed by RT-PCR, Northerns and finally, by binding assays using bona fide agonists. The Phase I benchwork for hypothesis 1 will be demonstration that MSH dimer binds with higher affinity and apparent cooperativity to MSH receptors, compared to MSH monomers. The benchmark for Hypothesis 2 will be production and testing of the array, and demonstration of at least one combination of receptors in PaAdo that is distinct from normal pancreas. In phase II, hypothesis 1 will continue to be tested in vitro and in vivo with trimers containing all four possible combinations of MSH, oxytocin, CCK and enkephalin. Hypothesis 2 will continue to be tested with a broader array of PaAdo and normal tissues. The two aims will be combined in the design and synthesis of multimeric ligands that specifically recognize PaAdo for eventual use in early detection or treatment of this terminal cancer. Although designed for PaAdo, these multimeric ligands could potentially be used against a wide variety of cancers.
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