This proposal selects five areas of astrocytoma biology and control that are particularly germane to our center: genetic abnormalities that characterize pediatric and adult astrocytomas; extracellular factors that inhibit astrocytoma invasion; immunoactive cytokines to control invasive astrocytomas; angiogenesis inhibitors as therapeutic agents for patients with astrocytomas; and stereotactic radiotherapy to achieve local control in adult and pediatric astrocytomas. The unifying goal of the proposal is to advance the management and basic understanding of astrocytomas in areas well developed in our group. To characterize pediatric and adult astrocytomas, molecular cytogenetic techniques will be used to define clinically relevant chromosomal abnormalities that underly astrocytoma formation and progression. The first of two projects that examine astrocytoma invasion into parenchyma will use genetic engineering techniques to mark invading cells and will then coinject cells secreting extracellular matrix with astrocytoma cells to identify what factors inhibit tumor invasion. The second project will use neuro-immunological techniques to identify and destroy microscopically invading tumor cells. Two programs will directly evaluate new treatment modalities. In the first, the potent new anti-angiogenesis agent AGM-1470 will be brought to clinical trial for the first time in brain tumors. This drug will also be used in the laboratory as an adjunct to traditional chemotherapeutic agents to create preliminary data for a possible potentiating role in astrocytoma therapy. The second program uses stereotactic radiotherapy, a technique that allows repeated highly focal radiation dosages, to develop an exciting new treatment program for benign and malignant astrocytomas. The project combines basic science and clinical research from the Brigham and Women's Hospital, Children's Hospital and Dana-Farber Cancer Institute to study astrocytoma biology relevant to clinical management and to evaluate innovative treatment modalities. As part of the Brain Tumor Center recently created at these institutions, it will provide the initial collaboration needed to produce an innovative and well-focused program in astrocytoma biology and management within three years.
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