Despite the many therapeutic modalities used in the treatment of malignant gliomas, the prognosis for these patients remain poor, with less than 10 percent of patients surviving beyond 2 years. The tumor cells' ability to invade the surrounding brain parenchyma lies at the core of the poor outcome. Our laboratory focuses on the mechanisms underlying glioma cell motility and invasiveness.
Specifically, we are interested in the role of epidermal growth factor receptor (EGFR), a frequently mutated oncogene in gliomas, and its effect on the expression of effector molecules (integrins and proteinases) that drive tumor invasion. EGFR appears to enhance invasion by at least two mechanisms. First, EGFR activity leads to the translocation of motility-associated integrins to the cells' plasma membrane, where they function as 'traction' molecules to guide cell movement. Second, EGFR enhances the expression of matrix metalloproteinases, such as MMP-1.
Current lab focus is on delineating the signaling pathways downstream of EGFR activation that leads to the observed effect on integrin and proteinase function. These basic science experiments and aims are complemented by a clinical focus on the development and evaluation of novel therapeutics. In this regard, we are currently evaluating an orally bioavailable EGFR inhibitor, ZD1839, in Grade 4 astrocytoma patients. This clinical study is scheduled to complete patient accrual in the Fall of 2002. Taken together, the laboratory science, meshed with the clinical translational objectives, constitute our laboratory's research directions.