Work on the role of insulin-like growth factors (IGFs) in pediatric sarcomas is continuing to focus on potential therapeutic approaches as well as further defining the downstream signaling events of IGF action. Testing on one newly developed monoclonal antibody demonstrated some activity against IGFIR signaling in cell lines, but we have elected to pursue work on another antibody as well as small molecular antagonists. Toward that end, we have developed a working group across the CCR to test IGFIR antagonists in preclinical models up through early Phase clinical studies. We are in the process of developing several partnerships with two companies who have developed several compounds of interest and are willing to work with our group for early development. Our studies will focus on using these compounds in metastatic mouse models of IGFII driven tumors (both human xenograft and murine tumors) as well as proteomic evaluation after IGFIR inhibition in human sarcoma cell lines. We have completed studies demonstrating that liver IGF-I deficient mice (LID mice) have decreased spontaneous metastases in an osteosarcoma model. This model involved bone marrow transplant, so we are currently working to develop the LID phenotype in a Balb/c mouse background to allow further studies on the role of IGF-I in metastatic behavior. We have continued to study the role of mTOR signaling in pediatric sarcomas. We have recently linked ezrin expression and metastatic potential (see below) to mTOR activation and have reported that mTOR blockade using CCI 779 in rhabdomyosarcomas inhibits primary tumor growth and inhibits mTOR signaling in the tumors. We have now also demonstrated that both rapamycin and CCI 779 inhibit metastases in our mouse osteosarcoma metastatic model, and have recently submitted this work for publication. Furthermore, we have analyzed 34 stage III human rhabdomyosarcoma tumors using reverse-phase proteomic analysis of 14 markers. All patients were treated uniformly on a national protocol and outcome data was available on all patients. We determined that activation of the mTOR pathway accurately predicted poor prognosis in these patients in a highly statistically significant manner. We plan to follow this study up with analysis of an additional 50 samples of Stage III patients from the same study. We have expanded our work on the role of ezrin in metastatic behavior, and have found that ezrin is highly expressed in Ewing's sarcoma. Current work is aimed at determining the functional role ezrin plays in these tumors.
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