EXCEED THE SPACE PROVIDED. The proposed studies use immunologic approaches to establish a more detailed understanding of the assembly and inhibition of oligomeric erbB transforming complexes relevant to human breast cancer. The working hypothesis is that disabling oligomers of erbB2 will be more effective than disabling erbB2 monomers in human breast cancer therapy. The initial intent is to define the basic molecular properties of erbB dimerization and tetramerization and determine the assembly patterns and functional differences between homomeric and heteromeric receptor ensembles. These differences will be exploited with dual specific monoclonal antibodies (MAb) that limit formation of transforming heteromeric tyrosine kinase complexes. Structural elements involved in erbB dimeric associations have been identified and may be appropriate targets for the creation of dual specific MAb that limit erbB oligomeric interactions. A new class of molecules that has been generated that represents mimetics of dimerization surfaces termed 'cystine knot mimetics' will be evaluated in vitro for their ability to disable the transition from monomers to dimers to tetramers seen in erbB complexes. As a second aim, the biochemical consequences of disabling dimer formation and dimer to tetramer transitions will be compared by studying induced alterations in the signaling pathways. Efforts will focus on the SIRPalpha-SHP2-phosphatidylinositol 3-kinase (PI 3-K) and PI 3-K related kinase (PIKK) pathways relevant to the maintenance of the transformed phenotype. Analysis of the events of the G2/M phase of the cell cycle which render erbB transformed cells resistant to genotoxic effects of radiation and chemotherapy will be pursued. Finally, the G2/M expressed survivin species and a newly cloned survivin associated molecule that link the erbB receptors to the behavior of the centrosome in mitosis will be analyzed. In the long term, an understanding of erbB oligomerization may lead to creation of more effective therapeutic antibodies for the treatment of breast cancer. PERFORMANCE SITE ========================================Section End===========================================
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