The goal of this project will be to identify genes with brain cancer or pathway specific expression that can be used as potential targets. This will include immunebased targeting by Projects 1 and 3 on this SPORE, as we1l as screens of small molecule inhibitors for this project. Using Serial Analysis of Gene Expression (SAGE) and real-time PCR, we will analyze the genes expressed specifically in the membrane bound polysomal mRNP fraction (destined for the cell surface) of glioblastomas to derive tumor-specific antigens for Project 1. We will use bioinformatics, real-time PCR and immunohistochemistry to locate and evaluate tumor markers specific astrocytic and oligodendro glioma tumors for a 'tumor vaccine' by Project 3. For this project we will evaluate the genes transcriptionally activated by EGFRvIII mutations in glioma cells, found in our laboratory using SAGE. These genes will provide biomarkers for inhibition of mutation specific activation. We have also recently identified carbonic anhydrase 9 (CA9) as a hypoxia activated gene in GBM [Lal, 2001 494]. We will evaluate existing therapeutics for CA9 and known carbonic anhydrase inhibitors. Finally, using a l0,000-plus small-molecule inhibitor library we will screen for inhibitors of genes and pathways that are involved in growth and invasion of gliomas to identify novel lead compounds. Specifically, we will search for those compound: that inhibit the transcription of genes normally activated by EGFRvIII and for inhibitors of the transcriptional activation of CA9. By combining SAGE with small-molecule screens we hope to locate inhibitors that target transcriptional activation specific to glioblastomas.
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