This is a Specialized Center of Research on human malignant gliomas and medulloblastomas. As detailed in the body of this application, these two nervous system neoplasms remain as significant health problems. Despite intensive research efforts by many investigators, there has been little progress made in the etiology, early diagnosis, or treatment of malignant primary brain tumors during the last 20 years. This Specialized Center of Research will continue the solidification of and intensification of the efforts of an outstanding group of internationally recognized investigators with a long history of effective collaboration. They will approach the malignant brain tumor problem in areas of etiology, mechanisms of altered growth control, diagnosis, pre-clinical, and clinical therapy. Projects range from: mechanistic studies on etiology, potential suppressor genes, and amplified and activated oncogenes in childhood brain tumors (Project IVa); to selection of glioma and medulloblastoma associated molecules for targeted therapy and growth inhibition (Project I); specifically production of anti- ganglioside and glycolipid monoclonal antibodies (Project Ia); analysis of new gangliosides and glycolipids and specificity analysis of anti-ganglioside mono-clonal antibodies (Ia1); development of operationally specific monoclonal antibodies against receptors and other proteins associated with glioblastomas and medulloblastomas (Project Ib); detailed study of the structure of the normal and abnormal epidermal growth factor receptor and its role in altered growth control in gliomas and medulloblastomas (Project Ic); protein biochemistry support for sequencing the proteins and epitopes under study in Projects Ib and Ic (Project Ib1, Ic1); to delivery of macromolecules and therapy of human glioma and medulloblastoma xenografts, specifically mechanisms of control of blood flow and permeability to normal brain and brain tumors (Project IIa); development of radiolabeled monoclonal antibodies for radioimmunotherapy of ana-plastic human glioma, medulloblastoma, and neoplastic meningitis (Project IIb); and increased delivery and therapy of human gliomas and medulloblastomas with radiolabeled monoclonal antibodies and drugs (Project IIc); to human therapeutic trials including intrathecal therapy of patients with neoplastic meningitis with radiolabeled monoclonal antibodies (Project III, IIIa, and IIIb); bifunctional alkylator therapy of medulloblastomas and childhood gliomas (Project IVb); to multiple modality clinical therapy trials with brain tumor patients in Projects Va, Vb, Vc, and Vd, including Phase I, Phase II, and randomized Phase III trials.
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