Soluble ligand binding domains of growth factor receptor tyrosine kinases (RTK) that are implicated in human cancer development and progression will be produced and characterized with respect to their ligand binding properties. The purified receptor domains will be provided to the University of Arizona Component (Dr. Kit Lam) for screening of peptide libraries using the technology described in that project. Peptide leads will be characterized (MPI,NYU) for their ability to bind to intact receptors overexpressed by transfected cells in culture and to activate their signalling function or to block binding of the natural ligand and thereby prevent receptor activation. Potentially antagonistic peptides will be tested in tumor growth inhibition assays (UA) (as well as at NYU and MPI for specific receptor systems). Initially, this approach will be applied to RTKs such as the EGF receptor, the oncogene product p185HER2/neu, and p145c-kit, for which strong evidence exists that implicates them in squamous carcinoma, mammary carcinoma, and acute myeloid leukemia. Analogous strategies will be pursued for novel receptor tyrosine kinases that are abnormally expressed in certain cancer tumors, after a crucial role in tumor progression has been established for them.
| Salmon, S E; Liu-Stevens, R H; Zhao, Y et al. (1996) High-volume cellular screening for anticancer agents with combinatorial chemical libraries: a new methodology. Mol Divers 2:57-63 |
| Nikolaiev, V; Stierandova, A; Krchnak, V et al. (1993) Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports. Pept Res 6:161-70 |
