GROWTH CONTROL IN PEDIATRIC TUMORS

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A major goal of this proposed program is the analysis, at the molecular level, of the factors that control growth of the most common childhood malignancies (leukemias, neuroblastomas and soft tissue tumors) in order to refine future therapeutic and prognostic approaches. An additional goal is to define genetic alterations within somatic cells that contribute to the cancerous phenotype in naturally occurring pediatric malignancies. Distinct genetic alterations in acute non-lymphocytic leukemia (ANLL) and in pre-B cell acute lymphocytic leukemias (pre-B-ALL) will be characterized. These changes will be exploited to monitor the extent of minimal residual disease of leukemia patients undergoing chemotherapy. In the case of ANLL with a mutated, and thus, activated ras oncogene, coupling of the polymerase chain reaction to generation and selective oligonucleotide screening of recombinant libraries will be utilized to evaluate the extent of minimal residual disease before completion of treatment. In the case of pre-B ALL with the t(9;22) translocation, the structural alterations involving the bcr-abl fusion product will be characterized by cDNA cloning and sequencing. This approach will identify the bcr break point; use of cDNA cloning and sequencing. This approach will identify the bcr break point; use of suitable oligonucleotide probes will allow efficient amplification of the bcr/abl translocation and be useful in detection and quantitation of residual leukemia cells. Molecular characterization of chromosomal translocation using inverted field gel electrophoresis, genomic cloning and chromosomal walking will also be the theme of the proposed studies in osteosarcomas and rhabdomyosarcomas with the final aim of identifying those genes responsible for the malignant progression of these diseases. The same soft tissue tumors, as well as neuroblastomas, will be utilized to determine the role played by the platelet-derived growth factor receptor and by the nerve growth factor receptor in controlling both normal and abnormal cellular growth and differentiation. In these solid tumors, the ultimate goal is to understand the contribution of abnormal growth factor receptor expression in contributing to abnormal cellular growth. Characterization of these abnormalities may provide clinically important prognostic variables for these tumors.