Medulloblastoma (MB) and related CNS primitive neuroectodermal tumors (PNETs) are the most common pediatric malignant brain tumors and major source of neurological morbidity and mortality in children. Despite the importance of this tumor and recent gains in developmental neurobiology and neurogenesis, the biology of MB and PNETs is poorly understood, treatment progress has stalled, and future advances will be contingent upon a greater understanding of the biology of these tumors, To address these problems, this Program Project aims to identify and characterize the role of neurotrophic growth factors and their cognate receptors (e.g., tropomyosin receptor kinases, TRK) in the regulation of proliferation, differentiation, and cell death in PNETs, and to exploit advances in knowledge of these processes to identify new prognostic information and therapeutic strategies. These overall objectives will be accomplished by the following projects. The first Project will produce TRK-specific monoclonal antibodies, and use these to characterized TRK expression and its functional and clinical significance in MB and related CNS PNETs. The second Project will evaluate the expression and function of TRK-B and -C in medulloblastoma and neuroblastoma, a peripheral nervous system PNET with many parallels to MB. The third Project will examine the role of tyrosine kinase signal transduction intermediates in the regulation of tumorigenesis and proliferation in MB. The fourth Project will focus on experimental therapies for leptomeningeal dissemination of MB, including new strategies which target receptor tyrosine kinases or their signal transduction pathways. A rich network of interrelationships links these projects and the thematic focus adds to the internal cohesiveness of this Program Project. Its feasibility is further enhanced by the addition of the New York University Neuro-Oncology Program to this Program Project. Medulloblastoma represents a robust model from which we may advance our understanding of normal and aberrant neurogenesis. Accordingly, the observations and results from Projects in this Program will have important implications for our understanding of developmental neurobiology and the biology and treatment of other primary brain tumors.
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