We have continued to focus on the role of insulin-like growth factors (IGF's) and tumor specific translocations in the pathogenesis of pediatric sarcomas, specifically rhabdomyosarcomas (RMS), Ewing's sarcomas/PNET (Ewing's family of tumors EFT), and osteogenic sarcomas (OS). We have recently confirmed that the fusion protein PAX3-FKHR generated by the tumor specific translocation of alveolar RMS leads to overexpression of IGF2 and an IGF binding protein (IGFBP-5) critical for IGF signaling. We have determined that the mechanism of PAX3-FKHR induced increase in IGF2 expression is indirect, since there is no evidence of direct binding to the region of the IGF2 promoter that is positively regulated by co-transfection studies. The mechanism and effect of increased IGFBP-5 expression due to PAX3-FKHR is currently under investigation. We have continued to utilize C2 mouse myoblasts overexpressing IGF2 to determine specific consequences of IGF2 overexpression in a muscle background. We have identified cabonic anhydrase 6 as overexpressed in C2 cells overexpressing IGF2 and are currently working to determine the significance of this finding. We are hoping to further analyze C2 cells with high IGF2 expression compared to normal C2 cells using cDNA microarray analysis. Recently, we have confirmed the overexpression of acetylcholine receptor gamma subunit in human rhabdomyosarcomas and are working to determine whether this can be exploited clinically. Finally, we are beginning to collaborate on a genetic model of rhabdomyosarcoma in mice, and have found that this model predicts abnormalities in the p16-CDK-4-cylcin D-Rb pathway in these tumors and have confirmed such abnormalities in human tumor specimens. We have now firmly established a mouse orthotopic model of osteosarcoma with spontaneous metastases, and are using cDNA microarray analyses to identify genetic determinants of metastasis in this model. We also continue to explore the potential role of combining growth hormone inhibition with chemotherapy in canine osteosarcoma, studying the hypothesis that lowering IGFI levels prior to cytotoxic chemotherapy will lead to increased apoptosis in tumor tissue dependent on IGFI for survival.
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