| Bronchioalveolar cancer (BAC) cannot be combated effectively either by surgery or by existing chemotherapies and patients typically die within 5 years of the diagnosis. This proposal seeks to investigate novel, mechanism-based strategies by which to inhibit BAC growth. Although the complete molecular mechanism by which a normal bronchioalveolar cell becomes cancerous is not yet understood, some key elements have been identified. Studies point to the mutation or over-production of the cell-surface proteins, EGFR and HER2 as causative events. There is, however, some discussion as to which of these proteins most correlates with severity of cancer, or even if the two together define the unique features of BAC. We propose to develop a strategy by which to inhibit the correct cellular folding and maturation of both EGFR and HER2. Our approach is to develop novel, small molecule inhibitors of the protein chaperone Hsp90, whose activity is essential for the folding and maturation of both EGFR and HER2. We also propose to compare the effects of our inhibitors alone, and in combination with a different Hsp90 inhibitor (17-AAG), EFGR kinase inhibitors (gefitinib) and HER2 inhibitors (Herceptin). The research we propose has great potential, not only to further elucidate the molecular basis of BAC but also for the development of a new class of anti-cancer agents for use in the treatment of BAC.
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