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The Plasminogen Activator System as a Target for Breast Cancer Virotherapy
Background: Oncolytic viruses are emerging as promising anticancer therapies. One example is the Edmonston vaccine strain of measles virus (MV). It exerts its cytopathic effects by formation of syncytia (multinuclear cell aggregates), resulting from fusion of infected cells, an effect mediated by the viral F and H glycoproteins. A clinical trial of MV in ovarian cancer is being conducted at our institution. The plasminogen activator (PA) system is involved in breast cancer (BC) progression. The urokinase receptor (uPAR) is overexpressed in BC, making it a biologically relevant target. We have shown that PAs induce antiangiogenic effects in vitro and in vivo and that overexpression of a proteolytically active, non-receptor binding uPA mutant (mutations in residues 27, 29, 30) is associated with reduced tumor progression and increased survival in a murine BC model. Hypothesis: Retargeting fusogenic viral glycoproteins to the uPAR will selectively induce tumor cytotoxicity and deliver therapeutic genes in breast cancer. Aims: 1) To engineer and characterize chimeric fusogenic glycoproteins targeted to uPAR. 2) To generate viral vectors retargeted to uPAR for BC treatment. 3) To assess the antitumor effects of targeted delivery of mutant uPA using redesigned oncolytic viruses. Methods: We will engineer chimeric MV-H glycoproteins with point mutations that impair their ability to attach to their native receptors (CD-46 and SLAM), to display the receptor binding (ATF, EGF) domains of uPA at its C terminus (HAALS-ATF; HAALS-EGF). Preliminary experiments have shown feasibility of uPAR mediated cell fusion and syncytia formation in uPAR expressing BC cells. The antitumor effects of the retargeted fusogenic glycoproteins will be assessed by introducing them into adenoviral vectors through in vitro ligation methods and into oncolytic MVs. The gene encoding “antitumor” mutant uPA will be introduced to retargeted measles virus. Studies will be performed in vitro to characterize their cytotoxic effects, and in orthotopic breast cancer models to assess the effects of the redesigned viruses on tumor progression, metastases, and survival. Implications: This is an innovative strategy for BC treatment, where uPAR serves as a target for fusogenic viruses, and the mutant uPA as a “novel agent” to amplify the virus’ antitumor effects. This study has potential to become a promising therapeutic tool for the management of advanced BC.
Despite advances in breast cancer treatment, thousands of women die of metastatic disease. Therefore, novel treatment strategies are urgently needed to improve the outcome of these patients. A promising new strategy for cancer treatment is the development of viruses that have potent antitumor effects. One example is a modified form of the measles virus, which has been shown to efficiently destroy tumors in animal models of cancer, and clinical trials using this virus are being conducted at our institution for diseases such as ovarian cancer. It has been established that the plasminogen activator system, a family of proteases (urokinase –uPA-, tissue plasminogen activator –tPA-) inhibitors (PAI-1), and receptors (uPA receptor) play an important role in breast cancer progression, and represents an attractive target for novel treatments. We have previously shown that the proteases tissue plasminogen activator and urokinase may actually induce antiangiogenic effects (blocking effects against blood vessels), both in animals and humans. Recently, using a mouse model of breast cancer, we found that a mutant form of uPA, when overexpressed in such tumors, is capable of blocking tumor growth, metastases, and significantly improving survival.
The goals of this innovative proposal are to “exploit” the relevance of the plasminogen activator system in breast cancer, and the potent antitumor effects of measles viruses to create novel “agents” for breast cancer treatment. To achieve these goals, I will develop variants of measles viruses that will be “retargeted” against cancer cells that carry the uPA receptor (overexpressed in breast tumors, but not in normal breast tissue). In preliminary studies, we have demonstrated the feasibility of this strategy. Additionally, the gene that produces the above mutant “antitumor” uPA will be introduced into the retargeted viruses, so that it is produced in high concentrations inside the tumors. This will enhance the viruses’ antitumor and antiangiogenic properties. Studies will be performed in human and mouse breast tumor cells, both in the test tube, and in mouse models of metastatic breast cancer, to assess the “redesigned” viruses’ abilities to destroy tumors, prevent tumor dissemination, and improve survival. This research may lead to innovative and effective biological treatments against breast cancer, with high potential to move into the clinic and bring new hope to patients with advanced disease.