Targeting Urokinase Pathway for Breast Cancer Therapy
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DESCRIPTION (provided by applicant): The underlying molecular mechanisms leading to breast cancer progression and maintenance of the malignant phenotypes may involve a growth factor-triggered signaling cascade leading to the activation of serine proteases. For example, overexpression of the EGF and HER2 receptors, and urokinase plasminogen activator (uPA) are frequently associated with an aggressive clinical course, shorter disease-free survival periods, poor prognosis, and increased metastasis in human breast cancer. More recently heregulin (HRG), a combinational ligand for HER3 and HER4 receptors, has been identified as an independent marker that predicts poor prognosis. In recent years, approaches involving interference with and/or blocking of HER-mediated autocrine/paracrine growth stimulation by anti-receptor mAbs have been the subject of active investigation to control the growth of breast cancer cell proliferation. Humanized mAb 225 (C225) and mAb 4D5 (Herceptin) are currently in phase II and phase III multicenter clinical trials, both alone and in combination with other anticancer agents. As for urokinase, because the activation of urokinase plasminogen activator (uPA)-dependent pericellular proteolysis and invasion depends on the localization of uPA to its receptor, uPAR, blocking this interaction may also lead to inhibition of tumor progression and angiogenesis. We purpose here to investigate the signaling pathways by which HRG regulates the expression and activation of the uPA/uPAR system, and to establish the clinical efficacy of a specific uPAR inhibitor (A36) either alone or in combination with C225 or Herceptin for suppressing breast cancer progression to more invasive phenotypes. Our working hypotheses are that "autocrine or paracrine activation of the uPA/uPAR system or HRG or both contributes to increased pericellular invasion of breast cancer cells; that this pathway may be positively influenced by the transactivation of HER2 and EGFR in tumor cells by the mesenchymal growth factor HRG; and that targeting uPA/uPAR with A36 and Herceptin or C225 may inhibit the progression of breast cancer." The rationale behind this proposal is based on the observations recently made by the Principal Investigator and colleagues that (i) HRG-stimulates the expression and activation of uPA/uPAR and invasion; (ii) a specific uPAR inhibitor (A36) blocked HRG-mediated invasion; (iii) A36 inhibited the VEGF promoter activity in breast cancer cells that have activated uPA/uPAR; (iv) A36 inhibited endothelial cell tube formation; (v) C225 and Herceptin blocked the uPAR expression in invasive breast cancer cells that have normal levels of EGFR and HER2; and (vi) HRG overexpression was associated with a short disease-free survival in patients with breast cancer. We believe that HRG, a mesenchymal growth factor, may have a significant role in the upregulation of uPAR on tumor cells by priming them for eventual activation of the uPA-uPAR cascade by uPA from stromal cells and combining the uPAR antagonist A36 with an anti-receptor mAb may enhance anti-invasive and anti-angiogenic properties/activity in vivo. The Specific Aims of this proposal are: (1) to determine the molecular mechanism by which HRG and the HERs regulate the uPA/uPAR system; (2) to examine the effects of A36 and Herceptin or C225 in preclinical in vitro and animals metastasis studies; and (3) to examine the significance of uPA/uPAR in relation to HRG as prognostic factors in human breast cancer. A unique aspect of our proposal is delineation of the mechanism by which HRG regulates uPA/uPAR and invasion, which will provide a novel rationale for therapy of metastatic human breast tumors by uPAR inhibitor and anti-receptor mAbs Herceptin or C225. These results will have a direct impact in developing novel therapeutic intervention strategies.
