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: Yuqi Jing, Marcela Toro Bejarano, Julia Zaias, Jaime R Merchan
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 149 Issue 1 Pg. 99-108 (Jan 2015) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 25519042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Urokinase Plasminogen Activator

Topics

• Administration, Intravenous
• Animals
• Breast Neoplasms (genetics, therapy, virology)
• Cell Line, Tumor
• Female
• Humans
• Mammary Neoplasms, Experimental (genetics, therapy, virology)
• Measles virus (genetics)
• Mice
• Neoplasm Metastasis
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics)
• Receptors, Urokinase Plasminogen Activator (antagonists & inhibitors, biosynthesis)
• Xenograft Model Antitumor Assays