This was the first and is now one of only two Specialized Research Centers of the National Institute of Neurological Diseases and Stroke on Primary and Metastatic Brain Tumors of Adults and Children. It is presently in its 20th year of funding and this application represents its fifth submission for competitive review and renewal. As detailed in the body of this application, both primary and metastatic tumors to the CNS remain as significant health problems and are actually increasing in magnitude. Despite intensive research efforts by many investigators, there has been little progress made in uncovering etiology or improving treatment of primary or metastatic brain tumors during the last 30 years. This Specialized Research Center on Primary and Malignant Tumors of the CNS will continue intensification of the brain tumor research efforts of an outstanding group of internationally recognized investigators with a long history of effective collaboration. In this application, primary and metastatic brain tumors in adults and children, both solid intracranial tumors and neoplastic meningitis, will be approached with novel therapeutic modalities. Projects include basic and preclinical studies in Project 1 directed at the development of radiolabeled MAbs and MAb fragments with Lutetium-177, a beta-emitter with favorable emissions that should minimize normal brain radiation; Project 2 which will introduce a genetically engineered poliovirus into clinical trial with brain tumors and neoplastic meningitis, and develop engineered alpha-Herpesviruses for brain tumor therapy; Project 3, which will discover mechanisms of DNA-interstrand crosslink repair mechanisms of resistance to chloroethylnitrosoureas and develop agents to reverse that resistance; and Project 4 will translate new treatment methods from Projects 1-3, D. Bigner's NCI MERIT Award, and M. Zalutsky's DOE Grant into Phase I and II clinical trials in patients with brain tumors and neoplastic meningitis. Core 1 will provide pre-clinical evaluation, IND's and clinical reagents, and Core 2 will provide administrative and general laboratory support.
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