The binding of a growth factor to its cellular receptor leads to activation of the intrinsic tyrosine kinase activity of the growth factor receptor. This increase in tyrosine kinase activity results in the tyrosine phosphorylation of substrates and leads to a mitogenic signal resulting in cell division. Studies with oncogenes have demonstrated that abnormalities in these signalling pathways can lead to cellular transformation, and many oncogenes encode mutationally activated tyrosine kinases. We hypothesize that the activation of growth factor receptors leads to transformation in CNS tumors and that activation of specific pathways correlates with patient outcome. We also hypothesize that there are specific tyrosine kinases activated in CNS tumors which have not been appreciated by previous studies. By making a systematic study, the importance of these potentially novel tyrosine kinases can be ascertained. Once these activated signalling pathways have been identified, it will be easier to direct specific therapies towards these receptor tyrosine kinases. The goal of this research is twofold: 1) To perform a systematic search of pediatric and adult CNS tumors for activation of the tyrosine kinase signalling pathway and to identify the specific growth factor receptor pathways that are being activated. 2) To correlate the activation of these pathways with patient outcome and tumor growth. We will screen tumor samples for the activation of growth factor signal transduction pathways. Since the intracellular signalling pathway utilized by many growth factors involves tyrosine kinase activity, we will assay for the presence of phosphotyrosine by immunocytochemistry. We will study both pediatric and adult tumors since pediatric astrocytomas tend to have a slower growth rate and a lower tendency to undergo malignant transformation. In those tumors that have increased phosphotyrosine, the activated tyrosine kinase (receptor or cytoplasmic) will then be identified. This approach can be utilized with a large number of CNS tumors, both pediatric and adult, including new and archival specimens. Concomitantly, we will examine the expression of specific growth factor receptors which our group and others have already shown are overexpressed in gliomas. It is well known that Epidermal Growth Factor Receptor is overexpressed in adult gliomas and our preliminary studies have also found overexpression of the EGF-R related receptor erbB2 (HER2/neu) in adult gliomas. We will examine the correlation between the expression of these receptors and clinical behavior of primary brain tumors. In combination with this, we propose to determine whether potential growth factor and growth factor receptor autocrine loops contribute to the growth of these tumors by determining the correlation between expression of EGF receptor and its ligand TGF-alpha with the proliferative index of the tumor. These studies will also be expanded to pediatric brain tumors.
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