title: In vivo anti-metastatic effects of uPAR retargeted measles virus in syngeneic and xenograft models of mammary cancer.
abstract: The urokinase receptor (uPAR) plays a critical role in breast cancer (BC) progression and metastases and is a validated target for novel therapies. The current study investigates the effects of MV-uPA, an oncolytic measles virus fully retargeted against uPAR in syngeneic and xenograft BC metastases models. In vitro replication and cytotoxicity of MVs retargeted against human (MV-h-uPA) or mouse (MV-m-uPA) uPAR were assessed in human and murine cancer and non-cancer mammary epithelial cells. The in vivo effects of species-specific uPAR retargeted MVs were assessed in syngeneic and xenograft models of experimental metastases, established by intravenous administration of luciferase expressing 4T1 or MDA-MD-231 cells. Metastases progression was assessed by in vivo bioluminescence imaging. Tumor targeting was evaluated by qRT-PCR of MV-N, rescue of viable viral particles, and immunostaining of MV particles in lungs from tumor bearing mice. In vitro, MV-h-uPA and MV-m-uPA selectively infected, replicated, and induced cytotoxicity in cancer compared to non-cancer cells in a species-specific manner. In vivo, MV-m-uPA delayed 4T1 lung metastases progression and prolonged survival. These effects were associated with identification of viable viral particles, viral RNA, and detection of MV-N by immunostaining from lung tissues in treated mice. In the human MDA-MB-231 metastases model, intravenous administration of MV-h-uPA markedly inhibited metastases progression and significantly improved survival, compared to controls. No significant treatment-related toxicity was observed in treated mice. The above preclinical findings strongly suggest that uPAR retargeted measles virotherapy is a novel and feasible systemic therapy strategy against metastatic breast cancer.
authors.affiliation: Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue, Suite 3300, Miami, FL, 33136, USA.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Jing
authors.forename: Marcela Toro
authors.initials: MT
authors.lastname: Bejarano
authors.forename: Julia
authors.initials: J
authors.lastname: Zaias
authors.forename: Jaime R
authors.initials: JR
authors.lastname: Merchan
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000628:therapy / Q000821:virology; D008459:Measles virus / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator