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 published the results of a randomized study of GH-IGF-I inhibition using a somatostatin analog in dogs with osteosarcomas. We hypothesized that lowering IGF-I levels would lead to increased apoptosis in tumor cells treated with standard chemotherapy. However, data from the 46 dogs randomized on this study failed to demonstrate either an increase in survival, or an increase in necrosis/apoptosis in doges randomized to the somatostatin analogue in spite of demonstrating a 50% decrease in circulating IGF-I in that cohort. We have therefore elected to not pursue this line of investigation further at this time. We have continued to utilize C2 mouse myoblasts overexpressing IGF2 to determine specific consequences of IGF2 overexpression in a muscle background. We have recently published our findings that IGF-II induced resistance to apoptosis is mediated in part through p70S6K signaling. This is reversed by rapamycin, and we are currently conducting preclinical studies in a mouse model of rhabdomyosarcoma and osteosarcoma to determine whether an analog of rapamycin, CCI-779, will improve survival in combination with standard cytotoxic therapy. We intend to measure inhibition of p70S6kinase activity and 4E-BP1 as molecular targets of this treatment. We are continuing to study the role of FKHR in mediating IGF related anti-apoptotic events as well, since this gene is altered in the t(2;13) translocation in alveolar rhabdomyosarcoma and appears to be an important signal in this pathway. We have found that FKHR phosphorylation appears to be uniquely regulated in these tumors compared to normal myoblasts. We are continuing 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. These data have recently been published. We have used cDNA microarray analysis to identify genetic determinants of metastasis in an established mouse orthotopic model of osteosarcoma with spontaneous metastases. . One gene identified that appears to be highly correlated with metastatic behavior is ezrin, a member of the ezrin-radixin-moesin family of proteinst that function as plasma membrane-cytoskeletal linkers. We have demonstrated in our animal model that blockade of ezrin leads to significantly decreased metastatic potential. We are now attempting to determine whether ezrin expression in human osteosarcoma may also correlate with metastatic potential.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006892-14
Application #
6756772
Study Section
(POB)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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