Mutations of the gene for epidermal growth factor receptor (EGFR) represent the most common oncogenic alteration in malignant gliomas. While the importance of aberrant EGFR activity in gliomas. While the importance of aberrant EGFR activity in glioma proliferation has been well documented, much less is known bout the impact of this receptor tyrosine kinase on the invasive behavior of gliomas, a feature while the importance of aberrant EGFR activity in glioma proliferation has been well-documented, much less is known about the impact of this receptor tyrosine kinase on the invasive behavior of gliomas, a feature that is intimately associated with the poor prognosis of these tumors. As part of a program to nurture the career development of a young neurologist clinician-investigator, we propose to test the postulate that mutations of EGFR that occur frequently in glioma enhance tumor invasiveness and that this biologic property can be inhibited by drugs that target EGFR signaling. Initial in vitro studies are directed towards determining which of the invasion-associated effector molecules (proteases, integrins) are stimulated by EGFR activity. To this end, our preliminary experiments have already shown that EGFR activation leads to increased invasion with a parallel increased expression of activated matrix metalloproteinase-9 (MMP-9), a known effector of glioma invasion. Building on these data, subsequent experiments are aimed at (i) delineating malignant gliomas; and (ii) determining whether aberrant EGFR expression in vivo confers enhanced tumor invasiveness. This project is the first step toward establishing a firm relationship between EGFR and the invasive phenotype of gliomas, and lays the foundation for the identification of novel therapeutics that target EGFR, as well as EGFR-regulated proteins that mediate the invasive phenotype in gliomas. The proposed project involves close interaction with an established mentor at an institution with a record of excellence in translational neuro-oncologic research. The candidate has already demonstrated potential for independent patient-based laboratory research, and with further training will develop a successful independent research program including clinically based laboratory research and translational clinical research in neurology.
| Giannini, Caterina; Sarkaria, Jann N; Saito, Atsushi et al. (2005) Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro Oncol 7:164-76 |
