The EGF receptor has emerged as a key target for rational therapeutic drug design. Over 60% of glioblastoma tumors express high levels and the extracytoplasmic deletion variant EGFRvlll is frequently present. There are now three FDA approved therapeutics against the receptor: two are tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, and the third is a monoclonal antibody, cetuximab (C225). However, the response rates for all of these drugs ranges from only 8-15%. Creating drugs that will more effectively target the EGFR is the next challenge. Our studies on EGFRvlll have highlighted two critical features regarding activation and oncogenicity that can potentially be exploited for targeting both EGFR and EGFRvlll.
In Specific Aim #1, we will identify the unique dimerization motif present in EGFRvlll. The recently solved crystal structure of the EGF receptor has revealed one mechanism for receptor dimerization but this is deleted in EGFRvlll. Identifying the motif by which EGFRvlll dimerizes will also suggests a strategy for disabling all EGFR family dimers.
For Specific Aim #2, we will determine the contribution of Golgi localization to the oncogenic properties of EGFRvlll and wtEGFR. The oncogenic signals of Ras originate from Golgi localized protein indicating that this localization is critical. We will test Golgi how the localization of EGFRvlll and EGFR contributes to their oncogenicity by directing receptor to the Golgi and then testing various downstream signaling molecules and parameters related to transfomation. We will also see if gefitinib and erlotinib have any differential sensitivity towards Golgi based receptor using cell fractionation studies and confocal microscopy.
In Specific Aim #3, we will synthesize this information to create therapies that will more effectively target EGFRvlll and wtEGFR in gliomas. First, we will generate a monoclonal antibody to the dimerization motif and determine its in various biologic assays. The effect of this monoclonal on tumor growth will be analyzed in comparison with cetuximab to confirm that it is more effective. Combination therapy with the monoclonal antibody will be performed with each TKI to demonstrate any synergy. Work on animal models will explore if a TKI is more effective at inhibiting Golgi based receptor. This work will reveal new insights into the properties of EGFR and EGFRvlll and will yield information that can be applied to the creation of new drugs and therapies for glioblastoma tumors. ? ? ?
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