EGFR (ErbB1) is a member of the ERBB farnily of proto-oncogenes, and whose overexpression/amplification has been reported in a variety of human cancers, including brain tumors. These studies suggest that alterations in the serum sErbB1/sEGFR concentrations may be useful in diagnosing cancer, in monitoring disease recurrence, and in predicting therapeutic responsiveness as well as disease outcome in patients with certain cancers. While the impact of the full length, membrane-anchored p170 EGFR in glioma biology has been well documented, relatively little, if any, reports exist in regards to soluble forms of EGFR (sEGFR) in brain tumors. Given that EGFR amplifications/mutations represent the most common oncogenic alterations in malignant gliomas, investigation of the relationship between serum levels of sEGFR and tumor burden could be of substantial benefit towards improving our ability to monitor this cancer, especially since brain tumors, by virtue of their anatomic location, are not amenable to repetitive tissue sampling. To that end, we pursue the hypothesis that sEGFR is a potential serum biomarker in malignant glioma patients. Our first objective (Aim 1) is to determine the relationship between serum levels of sEGFR and the tumor's size and molecular histology in an animal model developed by our Xenograft Core. The orthotopic xenograft model is unique in that the intracranially implanted tumors maintain the EGFR amplification observed in the patient tumor, in contrast to the loss EGFR-amplified cells in tissue culture. Tumor size will be measured both by serial MRI scans as well at autopsy. We will also evaluate sEGFR levels in animals undergoing pre-clinical treatment with small molecule inhibitors of EGFR combined with radiation (interface with Project 1) and with EGFR-targeted fusogenic measles virus (interface with Project 2).
In Aim 2, we will measure sEGFR levels in sera of GBM patients undergoing treatment in Mayo/NCCTG clinical studies investigating small molecule inhibitors of EGFR. We will also interface with the clinical trials proposed for Projects 1 and 2 to correlate sEGFR levels with patient outcome data. In addition intra-patient sEGFR measurements as a function of EGFR status and treatment type, we will also compare sEGFR among patient groups, with lower grades of tumors compared to GBM. This project merges the collective experiences and expertise of the PI (translational research pertaining to EGFR in glioma growth and invasion as well as clinical trials with EGFR inhibitors) and co-PI (identification and detection of sEGFR) to evaluate the potential role of sEGFR as a serum biomarker useful in the diagnosis and/or prognosis of high grade glioma patients.
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