Liu Ta-Chiang, Zhang Tingguo, Fukuhara Hiroshi, Kuroda Toshihiko, Todo Tomoki, Canron Xavier, Bikfalvi Andreas, Martuza Robert L, Kurtz Andreas, Rabkin Samuel D
Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Clin Cancer Res. 2006 Nov 15;12(22):6791-9. doi: 10.1158/1078-0432.CCR-06-0263.
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.
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.
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.
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.
溶瘤单纯疱疹病毒（HSV）似乎是一种很有前景的癌症治疗平台。然而，迄今为止，其作为单一药物的疗效并不理想。成纤维细胞生长因子（FGF）信号传导对于内皮细胞和肿瘤细胞的生长及迁移至关重要。在此，我们研究了用靶向FGF信号通路的显性负性FGF受体（dnFGFR）武装溶瘤HSV的策略。
通过转染构建了表达dnFGFR的小鼠Nf1:p53恶性外周神经鞘瘤（MPNST）细胞系。确定了dnFGFR表达对体外细胞生长和迁移以及体内肿瘤形成的影响。然后使用细菌人工染色体构建系统将dnFGFR转基因插入溶瘤HSV G47Delta中。检测了bG47Delta-dnFGFR的抗肿瘤和抗血管生成活性。
表达dnFGFR的MPNST 61E4细胞生长不如亲本对照细胞良好。与对照载体bG47Delta-empty相比，bG47Delta-dnFGFR在体外对肿瘤细胞（人U87胶质瘤细胞、F5恶性脑膜瘤细胞以及小鼠MPNST 61E4和37-3-18-4细胞）和增殖的内皮细胞（人脐血管内皮细胞和Py-4-1细胞）均显示出更强的杀伤作用，且不抑制病毒复制。在体内，bG47Delta-dnFGFR在抑制裸鼠体内人U87胶质瘤和小鼠37-3-18-4 MPNST肿瘤的生长和血管生成方面比其不表达的亲本bG47Delta-empty更有效。
通过利用包括破坏肿瘤细胞和肿瘤内皮细胞在内的多种治疗机制，编码dnFGFR的溶瘤HSV增强了抗肿瘤疗效。该策略可应用于其他溶瘤病毒并用于临床转化。
