761. Dominant-Negative FGF Receptor Expression by Oncolytic HSV Vector for the Treatment of Malignant Peripheral Nerve Sheath Tumors

Abstract

Top of pageAbstract Oncolytic herpes simplex viruses (HSV) have emerged as a promising platform for cancer therapy. Their large size permits insertion of therapeutic transgenes to augment the cytotoxicity of the backbone vector. Here we examine the activity of a dominant-negative FGF receptor (dnFGFR). Fibroblast growth factor (FGF) has been shown to stimulate the proliferation of Schwann cells in vitro, in addition to its mitogenic activity in endothelial cells, indicating its importance in malignant peripheral nerve sheath tumors (MPNST). We established MPNST cell lines transformed with dnFGFR or the control plasmid and showed that dnFGFR decreased cell proliferation and migration in vitro and reduced vascularity and delayed tumor growth in vivo. The dnFGFR transgene was inserted into oncolytic HSV G47|[Delta]| (deleted in |[aacute]|47/Us11 promotor, |[gamma]|34.5, and a LacZ insertion inactivating ICP6), using the G47|[Delta]|-BAC (bacterial artificial chromosome) system. G47|[Delta]|-dnFGFR showed enhanced killing of both tumor and proliferating endothelial cells in vitro compared to the G47|[Delta]|-empty control vector. In vivo, G47|[Delta]|-dnFGFR was more efficacious than it's non-expressing parent G47|[Delta]|-empty at inhibiting MPNST growth. Therefore oncolytic HSV encoding antiangiogenic dominant-negative FGFR transgene is a new strategy for tumor treatment.