Mechanisms of Glioma Invasion and Signal Transduction Inhibitors
Although many of the genetic alterations that dysregulate the cell processes of growth and death involved in tumor initiation have been elucidated in recent years, less progress has been made in the complex but critical processes of tumor invasion, metastasis, and angiogenesis. Invasion is particularly important in the pathophysiology of gliomas, as tumor cell infiltration of normal brain prevents curative resection. With this emphasis, Drs. Jeremy Rich and Henry Friedman are currently investigating the roles of extracellular matrix proteins and related signal transduction pathways in glioma invasion. Specifically, the investigators have developed genetically defined human glioma cell lines and transgenic murine glioma models with which they are investigating the contributions of secreted protein acidic and rich in cysteine (SPARC) and transforming growth factor (TGF) to the invasive phenotype. The investigators are currently interrogating the models to determine the contributions of specific signal transduction pathways to the ability of these gene products to alter invasion, proliferation, and resistance to apoptosis. They are further examining the potential ability of inhibitors of these pathways to modify the phenotype, laying the potential foundation to novel therapeutic approaches in the treatment of malignant gliomas.
As an extension of their interests in signal transduction pathways, researchers have developed a program to investigate the potential utility of small molecule inhibitors of elements of pathways that contribute to the phenotype of malignant gliomas in conjunction with the laboratory of Dr. Henry Friedman. Specifically, inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), Raf kinase, TGF receptors, and mammalian target of rapamycin have shown significant promise in both cell culture and immunocompromised rodent xenograft studies. Current studies involve the determination of cellular sensitivity to these agents and utility of a combinatorial approach with multiple signal inhibitors or inhibitors with cytotoxic agents. These results have already formed the groundwork for novel clinical trial designs.