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

Abstract

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 G47D using a bacterial artificial chromosome construction system. Antitumoral and antiangiogenic activities of bG47D-dnFGFR were examined. Results: MPNST 61E4 cells expressing dnFGFR grew less well than parental control cells. bG47D-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 bG47D-empty without inhibiting viral replication. In vivo, bG47D-dnFGFR was more efficacious than its nonexpressing parent bG47D-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.

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

“…7,8 We found that TSA had a suppressive effect on the growth of oral SCC cells at 0.3 mM, but its effect was insufficient at 0.1 mM. When TSA was combined with R849, cell viability was decreased more strongly than with R849 only, indicating that TSA promoted the antitumor activity of the g 1 34.5 genedeficient HSV-1 mutant.…”

“…Thus, recent studies have focused on the effect of combining oncolytic virotherapy with chemotherapy or construction of viruses encoding therapeutic transgenes. [4][5][6][7][8][9] The ubiquitous nuclear factor NF-kB is a critical regulator of the expression of numerous genes implicated in immune and inflammatory responses, cellular proliferation and differentiation and cell survival. 10,11 It is activated by a broad variety of stimuli, such as growth factors, cytokines, ionizing radiation, ultraviolet light, chemotherapeutic drugs and bacterial and viral infections.…”

Gene therapy progress and prospects cancer: oncolytic viruses

“…19 Oncolytic HSV encoding dominant-negative fibroblast growth factor receptor or antiangiogenic protein platelet factor-4 led to significant reduction in tumor vasculature and as a result, significantly enhanced therapeutic efficacy. 20,21 Others have engineered oncolytic virus replication to be activated by tumor matrix metalloproteinases (MMP), 22 and shown that MMP-8 gene delivery enhanced the efficacy of oncolytic adenovirus. 23 An alternative approach is to coadminister therapeutic agents with the virus.…”

“…31 It has also been shown that adenovirusinduced ERK activation is critical to viral replication. 43 Oncolytic viruses can also be 'programmed' to replicate in cells through certain cellular signaling activities, such as b-catenin, 44 to carry therapeutic transgene that targets tumorigenic pathways, 20 or retargeted to cellular receptors that are essential for signaling (for example, epidermal growth factor receptor (EGFR)). 45 Novel oncolytic virus species are being explored As most oncolytic viruses have produced less than optimal efficacy in clinical trials as single agents, there is great interest in exploring novel viral species.…”

Experimental therapeutic approaches to peripheral nerve tumors

“…Subsequent studies have examined incorporation of specific transgenes designed to augment the oncolytic HSV-mediated tumor cell killing capacity. Liu et al 87 have demonstrated that incorporation of the dominant-negative FGF receptor into an oncolytic HSV resulted in improved killing of both MPNST cells and endothelial cells as compared with the effect of oncolytic HSV alone or transfection with dominant-negative FGF receptor alone, when studied in vitro. The oncolytic HSV with dominant-negative FGF receptor demonstrated greater in vivo inhibition of angiogenesis and tumor growth than did an oncolytic HSV vector without the dominant-negative FGF receptor.…”