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Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors

Authors' Affiliations: ¹ Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts and ² Institut National de la Santé et de la Recherche Médicale E0113, Molecular Mechanisms of Angiogenesis, University Bordeaux I, Talence, France

Requests for reprints: Samuel D. Rabkin, Molecular Neurosurgery Laboratory, Massachusetts General Hospital, CPZN-3800 Simches Research Building, 185 Cambridge Street, Boston, MA 02114. Phone: 617-726-6817; Fax: 617-643-3422; E-mail: rabkin{at}helix.mgh.harvard.edu.

Purpose: Oncolytic herpes simplex viruses (HSV) appear to be a promising platform for cancer therapy. However, efficacy as single agents has thus far been unsatisfactory. Fibroblast growth factor (FGF) signaling is important for the growth and migration of endothelial and tumor cells. Here, we examine the strategy of arming oncolytic HSV with a dominant-negative FGF receptor (dnFGFR) that targets the FGF signaling pathway.

Experimental Design: A mouse Nf1:p53 malignant peripheral nerve sheath tumor (MPNST) cell line expressing dnFGFR was generated by transfection. The effects of dnFGFR expression on cell growth and migration in vitro and tumor formation in vivo were determined. The dnFGFR transgene was then inserted into oncolytic HSV G47 using a bacterial artificial chromosome construction system. Antitumoral and antiangiogenic activities of bG47-dnFGFR were examined.

Results: MPNST 61E4 cells expressing dnFGFR grew less well than parental control cells. bG47-dnFGFR showed enhanced killing of both tumor (human U87 glioma and F5 malignant meningioma cells and murine MPNST 61E4 and 37-3-18-4 cells) and proliferating endothelial cells (human umbilical vascular endothelial cell and Py-4-1) in vitro compared with the control vector bG47-empty without inhibiting viral replication. In vivo, bG47-dnFGFR was more efficacious than its nonexpressing parent bG47-empty at inhibiting tumor growth and angiogenesis in both human U87 glioma and mouse 37-3-18-4 MPNST tumors in nude mice.

Conclusions: By using multiple therapeutic mechanisms, including destruction of both tumor cells and tumor endothelial cells, an oncolytic HSV encoding dnFGFR enhances antitumor efficacy. This strategy can be applied to other oncolytic viruses and for clinical translation.

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