The malignant behavior of neuroblastomas differs markedly: some regress spontaneously, others can be eradicated with therapy, and still others respond temporarily or not at all to therapy.
The aims of this investigation are to further understand the molecular basis for these differences and to use this information to improve diagnosis and prognostication. The relationship of oncogene expression, tumor cell proliferation, and patient survival will be examined and monoclonal antibodies against tumor cell markers that define neuroblastoma and its biologically and therapeutically relevant subsets will be characterized. Laboratory and clinical resources include 1) panels of monoclonal antibodies, oncogene probes, and human neuroblastoma cell lines; 2) microcomputer-based digital image microscopy; 3) a unique and enlarging library of tumor and bone marrow specimens; and 4) a computerized clinical database for patients being studied. Our previous studies of the N-myc oncogene documented that tumors with genomic amplification rapidly progress; that the gene product is a nuclear phosphoprotein (62 and 64 kd); and that tumors with greater than 10 copies of the gene express high amounts of the protein. Our new studies will determine if a significant percentage of non- amplified, aggressive tumors express N-myc and if progression of amplified or non-amplified tumors is associated with increased expression. Additional important experiments aim to identify other oncogenes that are activated, particularly in those aggressive tumors that do not express N-myc. A major consequence of activating N-myc and other oncogenes may be to confer greater proliferative capacity, which results in a highly malignant phenotype. We shall seek support for this hypothesis by determining if there is a relationship between N-myc expression and antigens that define the proliferative state of tumor cells. By immunophenotyping, we shall determine if oncogene, differentiation antigen, and histocompatibility antigen expression defines biologically and therapeutically relevant subtypes of neuroblastomas and primitive neuroectodermal tumors. Our prognostic efforts seek to further improve accuracy by focusing on antigenic markers for oncogene proteins and cell proliferation- related molecules. The relative importance of known factors and those to be tested will be determined by multivariate analysis. Throughout our studies of prognosis, we shall determine if previously unrecognized subsets of patients emerge as a result of new therapies. We anticipate that these studies will contribute to the understanding of neuroblastoma and ultimately to therapeutic modalities that are more effective and specific.
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