There are no effective therapies for malignant brain tumors, the number one killer among children with cancer. In order to develop effective therapies, the mechanisms that control tumor growth must be understood. Accelerated growth of a variety of neural tumors has been correlated with overexpression of receptors for the epidermal growth factor (EGF) or fibroblast growth factor (FGF). The overexpression of these growth factor receptors is thought to result in autocrine growth of the tumors. Ganglioside GM3 is able to specifically inhibit cell growth and tyrosine specific kinase activity associated with the receptors for these growth factors. It is our hypothesis that GM3 mediates its effects by binding directly to the receptor protein, and that it inhibits receptor activation and signal transduction. The overall aim of this proposal is to understand the mechanism of GM3 inhibition and to make use of this mechanism for possible therapeutic applications in brain tumors. To accomplish these goals we will: l) generate deletion and point mutations of the EGF receptor and stably express these mutant receptors in mammalian cells; 2) determine if exogenously added GM3 will effect the growth and protein tyrosine kinase activity of these mutant receptors; 3) determine if GM3 interacts directly with the EGF receptor in these cells; and 4) examine the mechanism of GM3 inhibition of the EGF and FGF receptors. The long term goal of this research is to understand how changes in ganglioside composition may influence the growth behavior of brain tumors. The altered expression of gangliosides is a phenomenon found in virtually all tumors. The possibility that ganglioside GM3 may interact directly with the EGF receptor suggests that it may be possible to exploit this mechanism of inhibition for future therapeutic applications in brain tumors. It may be possible to block signal transduction of these growth factor receptors in brain tumors by gangliosides, thus reducing the autocrine growth advantage that these tumors may attain by receptor overexpression. This project is one of four sections of an Interactive Research Project Grant (IRPG) application, Glycobiology of Brain Tumors, to the National Cancer Institute (PA-93-078). The overall goals of this interactive project are: l) test the hypothesis that brain tumor gangliosides may play a key role in tumor development and progression; and 2) modulate their expression by several complementary approaches.
