This proposal is to develop a Brain Tumor Research Center at Case Western Reserve University and University Hospitals of Cleveland whose central focus will be the development application of membrane targeted, peptide toxins to improve therapy for malignant brain tumors. The proposal constitutes a synergistic, interdisciplinary, interaction of the clinical, scientific and organizational expertise of physicians and scientists from the Departments of Neurosurgery, Neurology, Neurosciences, Molecular Biology, Medicine, Pediatrics and the Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University. Project 1 will examine the fundamental role of the epidermal growth factor receptor (EGF-R) and the associated signal transduction processes in establishing and maintaining the transformed state in gliomas. Project 2 will examine the role of neurotrophins and the trk family of protooncogenes for their role in growth promotion and establishment of the malignant state in primitive neuroectodermal tumors and astrocytomas. Project 3 will analyze human brain tumors for activation of a specific series of oncogenes including PDGF, Gli and acidic and basic FGF, postulated to be involved in promoting glial cell proliferation. This project will also establish brain tumor derived, human cell lines and test representative samples to evaluate the growth regulating effect of interfering with function and/or expression of these oncogenes. Project 4 will examine the in vitro and in vivo cytotoxic effects of a series of fusion protein constructs, composed of epidermal growth factor (EGF) fused with bacterial exotoxins, on human brain tumors bearing the EGF receptor. Project 5 will develop and test monoclonal antibodies with specificity for malignant astrocyte determinants for their cytotoxic effects on brain tumors. The program will promote the multidisciplinary clinical management of patients with brain tumors and will serve to foster technology transfer from research lab to clinical trials.
