The central goal of this project is to establish a center for basic and clinical brain tumor research. Specific emphasis has been placed on studies of the molecular and cellular biology of anaplastic glial tumors, and on investigational treatment programs for patients affected by these tumors. Project No.1 is concerned with expression of tumor necrosis factor-alpha (TNFalpha) in malignant glioma cells. Studies will focus on induction of TNFalpha gene expression by interleukin-1, on transcriptional control elements involved in TNFalpha expression, and on the effects of TNFalpha on glioma cell biology. Project No.2 will examine the role of transforming growth factor-beta (TGFbeta) in the cellular biology of glioma cells. Studies will focus on purifying, cloning, and characterizing a novel high-molecular weight form of TGFbeta expressed by human gliomas and glioma cell lines. Project No.3 is concerned with characterizing the expression of vitronectin and of the vitronectin receptor integrins by glioma cells in situ and in vitro. The functional role of these integrins in adhesion and invasiveness of glioma cells will be studied, as will the effects on glioma cells of blocking integrin function. Project No.4 will examine the molecular basis for the motility and invasiveness of glioma cells. Studies will focus on the functional topology of glioma-derived myosin II, and on the inhibitors of myosin II and integrin function as potential antagonists of glioma cell invasiveness. Project No.5 will continue the active clinical efforts at UAB to develop better therapy for patients with malignant gliomas. Treatment programs will include intra- arterial cisplatin chemotherapy, intensive systemic chemotherapy, biologic response modifiers, and studies of the safety and efficacy of an anti- epidermal growth factor receptor monoclonal antibody. In addition, the practical clinical usefulness of single photon emission computed tomography (SPECT) imaging of malignant gliomas and the biologic insights provided by this technique will be studied. Core A, the Administrative Core, will facilitate interactions among the group members, and will be responsible for the overall management of the project.
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