Dominant-negative fibroblast growth factor receptor expression enhances antitumoral potency of oncolytic herpes simplex virus in neural tumors.
OBJECTIVE
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.


METHODS
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 G47Delta using a bacterial artificial chromosome construction system. Antitumoral and antiangiogenic activities of bG47Delta-dnFGFR were examined.


RESULTS
MPNST 61E4 cells expressing dnFGFR grew less well than parental control cells. bG47Delta-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 bG47Delta-empty without inhibiting viral replication. In vivo, bG47Delta-dnFGFR was more efficacious than its nonexpressing parent bG47Delta-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.
Liu
Ta-Chiang
TC
Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Zhang
Tingguo
T
Fukuhara
Hiroshi
H
Kuroda
Toshihiko
T
Todo
Tomoki
T
Canron
Xavier
X
Bikfalvi
Andreas
A
Martuza
Robert L
RL
Kurtz
Andreas
A
Rabkin
Samuel D
SD
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000628:therapy*; D002465:Cell Movement; D049109:Cell Proliferation; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000378:metabolism; D005799:Genes, Dominant; D005822:Genetic Vectors / Q000502:physiology / Q000627:therapeutic use; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015398:Signal Transduction; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins