The epidermal growth factor receptor (EGFR) is overexpressed during bladder cancer progression, andclinically relevant EGFR antagonists inhibit the growth of tumor xenografts in vivo. However, EGFRinhibitors not displayed consistent activity in clinical trials performed in other disease sites, which hasdampened clinical enthusiasm for aggressively developing them further. Studies performed within thecontext of non-small cell lung cancer demonstrated that clinical responses were linked to activatingmutations within the EGFR tyrosine kinase domain, suggesting that a better understanding of the biologicaleffects of EGFR inhibitors on tumor cells will help to identify tumors that will respond (biologically or clinically)to therapy. In preliminary studies conducted during the first cycle of SPORE funding, we found that EGFRinhibitors (gefitinib or cetuximab) blocked cell cycle progression in 8/20 human bladder cancer cell lines, andwe have identified molecular mechanisms that appear to mediate these effects. Although none of the celllines nor any of 75 primary tumors contained activating EGFR kinase domain mutations, preliminary datasuggests that over 50% of primary tumors express a truncated form of the EGFR (EGFRvlll) that mediatesligand-independent signaling and promotes tumor growth in other model systems. Therefore, the overall goalof this project is to define the biological properties associated with EGFR-dependent growth in bladdercancer cells and to develop pharmacodynamic markers that can be used to monitor them in tissue biopsiesharvested during therapy. To this end, we propose 4 Specific Aims. (1) Define the molecular mechanismsunderlying the antiproliferative effects of EGFR inhibitors in urothelial carcinoma cells. (2) Determine thefunctional significance of EGFR-vlll expression in urothelial carcinoma. (3) Define the role of the hostresponse in the angiogenesis inhibition observed in response to EGFR-directed therapy. (4) Evaluate theactivity of combined therapy with EGFR inhibitors and TRAIL. An important component of this project is aclinical trial designed to test the effects of cetuximab on pharmacodynamic markers in primary tumors. Thus,we are in a unique position to directly test the validity of the hypotheses we have generated in our preclinicalstudies and to exploit them in the design of more effective, EGR-based therapeutic strategies.
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