Tumor cells recruit normal endothelial cells (ECs) in the tumor microenvironment, a process which is essential for continued growth and spread of tumors. Numerous oncogenic signaling pathways, including the Src oncoprotein, induce expression of angiogenic factors such as vascular endothelial growth factor (VEGF) that promote tumor angiogenesis. We have shown that the Src kinase regulates VEGF expression through activation of Stat3 signaling in tumor cells. Furthermore, Stat3 is one of the major signaling pathways downstream of Src that is frequently activated in many human tumors, including melanoma and sarcoma. We propose that Src and downstream Stat3 signaling are essential not only for tumor cell survival but also for production of angiogenic factors and their actions on ECs in the tumor microenvironment. Thus, the recent development of clinically-promising pharmacologic Src inhibitors sets the stage for testing a new generation of antitumor and antiangiogenesis therapeutics. The central hypothesis of this proposal is that inhibitors of Src kinase and downstream Stat3 signaling will induce tumor regression through both direct tumor cell apoptosis and impairment of tumor angiogenesis. We will address this hypothesis using a new generation of orally-bioavailable pharmacologic Src inhibitors that are already in early-phase clinical trials. Our focus will be on melanoma and sarcoma because we have shown the important role of Src and downstream Stat3 signaling in these tumor cells. Furthermore, there is a need for more effective therapies in malignant melanoma and sarcoma. The studies proposed here will investigate the molecular mechanisms of action of novel pharmacologic Src kinase inhibitors through the following specific aims: (1) determine the biological effects of Src kinase inhibitors on growth and survival of human melanoma and sarcoma cell lines in culture;(2) assess how inhibition of Src signaling effects production of angiogenesis factors by tumor cells and response to them in tumor ECs;(3) evaluate the effects of Src inhibitors on tumor regression and tumor vasculature in animal models of human melanoma and sarcoma;(4) validate the potential relevance of activated Src signaling in human melanoma and sarcoma clinical specimens. In sum, these studies will provide insights into the mechanism of action of a new generation of pharmacologic Src kinase inhibitors and thereby lay the foundation for more effective molecular-targeted therapy of melanoma and sarcoma.
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