GROWTH REGULATING GENES IN PRIMITIVE NEUROECTODERMAL TUMORS

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Medulloblastoma is the most common malignant brain tumor of childhood. It is thought to originate from the progenitors of granule cell neurons cell neurons in the developing cerebellum and it is classified as a primitive neuroectodermal tumor. About half the children and young adults with this disease survive longer than 10 years following surgery and adjuvant therapy. The others relapse and die in the face of identical treatment. Several years ago, we and our colleagues discovered a prognostic indicator for medulloblastoma. We showed that "standard risk" medulloblastomas express high levels of mRNA encoding the neurotrophin-3 receptor protein TrkC. The "high risk" medulloblastomas express low levels of trkC. The experiments we describe here are based upon this observation. We have three specific aims. The first aim is to establish the cellular basis for trkC over-expression in standard risk versus high risk medulloblastomas. Do standard risk tumors contain a greater percentage of cells that express trkC mRNA, or do the cells within these tumor express more trkC mRNA per cell? Quantitative analysis using in situ hybridization and immunohistochemical assays will be used to address this question. This will elucidate whether high and low trk C tumors represent two distinct types of medulloblastoma or sequential stages in the evolution of a common medulloblastoma progenitor. The second specific aim is to determine whether a prognostic correlation can be made with TrkC protein per se or with TrkC signaling functions. We will use phosphotyrosine directed antibodies to determine whether TrkC signaling functions are active in standard risk tumors in vivo. This will be an important step in learning whether activation of TrkC inhibits tumor growth. The third specific aim is to determine which other genes are coordinately up-regulated along with trk C in standard risk versus high risk medulloblastomas. Towards this end we will use a large cohort of standard and high risk medulloblastomas to screen the clones isolated by Dr. Stiles based on their differential expression in a high risk and standard risk tumor. Taken together the studies outlined here will provide a basis for understanding molecular attributes that enable some patients with medulloblastoma to be cured of their disease.