By studying glioma tumors, we expect to make correlations with clinical outcome that will shed light on the malignant phenotype, the propensity of some tumor types to invade and/or metastasize, and uncover potential future molecular targets for therapy. Our clinical aims are to (1) develop innovative therapeutic protocols for patients to increase the length and to enhance the quality of survival; (2) develop and validate dynamic magnetic resonance imaging (MRI) and segmentation techniques to better separate radiation-chemotherapy neurotoxicity from tumor growth and use these and other newer MRI techniques to describe phenotypic changes in tumors after antiangiogenesis and anti-protease therapies; (3) monitor the quality of life, cognitive function, emotional status, and functional status of brain tumor patients over the course of their disease and treatment to define the relative risk and benefits for subgroups of patients; (4) compare the observed incidence of cancer among relatives of glioma patients with that expected in the general population and evaluate a perceived excess of pancreatic cancer in relatives of glioma patients; (5) determine characteristics associated with increased cancer risk and determine genetic heterogeneity in kindreds by molecular genetic and other unique patient covariates and characterize the mode of inheritance of gliomas; (6) confirm that probands with second malignancies and/or multifocal gliomas represent a genetically predisposed high-risk subgroup; and (7) determine in tumor biopsies amounts of Ki-67 (mib-1 Ab) and p53 protein. Our laboratory aims are to (1) determine the extent of p53 and p16 gene alterations in tumor biopsy material and in the germ line of patients (and their families); (2) determine the expression and alteration of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor-alpha in gliomas and brain adjacent to tumor and the modulation of the expression of bFGF and VEGF using various antigene, antisense, and ribozyme approaches; (3) identify the region on chromosome 4 that contains a tumor suppressor gene; (4) use high-saturation alleotyping and gene alteration analysis on selected patients to uncover unique gene alterations; (5) determine the levels and cellular localization of serine proteases, metalloproteases, cysteine proteases, and their inhibitors in patients with gliomas of differing histologies and outcomes; and (6) determine the effect of antibodies, protease inhibitors, and chemical inhibitors on the invasive behavior of primary glioma cultures.
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