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. ? ? ?
|Emlet, David R; Gupta, Puja; Holgado-Madruga, Marina et al. (2014) Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III. Cancer Res 74:1238-49|
|Del Vecchio, C A; Giacomini, C P; Vogel, H et al. (2013) EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene 32:2670-81|
|Giacomini, Craig P; Sun, Steven; Varma, Sushama et al. (2013) Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types. PLoS Genet 9:e1003464|
|Del Vecchio, Catherine A; Jensen, Kristin C; Nitta, Ryan T et al. (2012) Epidermal growth factor receptor variant III contributes to cancer stem cell phenotypes in invasive breast carcinoma. Cancer Res 72:2657-71|
|Del Vecchio, Catherine A; Li, Gordon; Wong, Albert J (2012) Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev Vaccines 11:133-44|
|Piccione, E C; Lieu, T J; Gentile, C F et al. (2012) A novel epidermal growth factor receptor variant lacking multiple domains directly activates transcription and is overexpressed in tumors. Oncogene 31:2953-67|
|Nitta, R T; Del Vecchio, C A; Chu, A H et al. (2011) The role of the c-Jun N-terminal kinase 2-?-isoform in non-small cell lung carcinoma tumorigenesis. Oncogene 30:234-44|
|Monje, Michelle; Mitra, Siddhartha S; Freret, Morgan E et al. (2011) Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci U S A 108:4453-8|
|Nitta, Ryan T; Badal, Shawn S; Wong, Albert J (2010) Measuring the constitutive activation of c-Jun N-terminal kinase isoforms. Methods Enzymol 484:531-48|
|Gupta, Puja; Han, Shuang-Yin; Holgado-Madruga, Marina et al. (2010) Development of an EGFRvIII specific recombinant antibody. BMC Biotechnol 10:72|
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