By studying patients with gliomas, we hope to make correlations with clinical outcome that will shed light on malignant phenotype, the propensity of some tumor types to invade and/or metastasize, the control of tumor lineage, relevant germ line mutations, and uncover potential future molecular targets for therapy. Surgical biopsy material and early passage glioma cells from patients with different adult and childhood brain tumors will be used to determine amounts of cytokine and cytokine receptors, cell proliferation, the glutathione content, expression of glutathione-S- transferases, the activity of O6-methylguanine-DNA-methyltransferase, DNA polymerase alpha and beta, topoisomerase II, and the ability of tumor cells to repair DNA interstrand crosslinks after in vitro exposure to nitrosourea and platinum compounds. We will also investigate tumor invasiveness in histologic sections and compare this with invasiveness as judged by neuroimaging studies. The suppressor gene associated with chromosome 10 will be determined. We will investigate the effect of reinsertion of EGFR, TGFalpha, and p53 genes and chromosome 10 into normal glial cells, astrocytoma, and glioblastoma cells on phenotype, alterations in expression of EGFR, FGF, and TGFbeta, tyrosine protein kinases, and nuclear c-myc and c-fos expression. These same parameters will also be studied following exposure to retinoic acid, herbimycin, and other potential differentiating agents. The extent of p53 gene alterations in tumors and in the germ line of patients and the differential expression of type I and type II NFI transcripts will be explored. Family kindreds of glioma families with cancer will also be studied to determine relevant familial and de novo germ line mutations. In addition to these laboratory studies, we will develop aggressive and innovative clinical therapeutic trials for patients with primary malignant brain tumors in order to improve total survival and enhance quality of survival.
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