Therapy of Experimental Nerve Sheath Tumors Using Oncolytic Viruses

摘要

Peripheral nerve sheath tumors are the major tumors in neurofibromatosis type 1 (NF1). Malignant transformation of these tumors leads to extremely poor prognosis without therapy. The main goal of this project is to determine the efficacy of recombinant oncolytic herpes simplex type 1 viruses (HSV) for the therapy of nerve sheath tumors. To that aim we will generate reliable tumor models for malignant peripheral nerve sheath tumors (MPNST). Several existing and novel oncolytic HSV vectors will then be tested on these models for therapeutic utility. To examine the combination of anti- angiogenic and oncolytic virus therapy, recombinant G47 deta vectors expressing anti- angiogenic factors dominant-negative fibroblast growth factor receptor (dnFGFR) and platelet factor 4 (PF4) have been generated. Expression of dnFGFR from G47 deta increases cytotoxicity in vifro to human endothelial cells and murine Nf1 MPNST cell lines. Inhibition of MPNST M2 tumor growth in vivo was significantly enhanced by the expression of dnFGFR or PF4 compared to G47 deta alone. This provides support for the clinical application of this novel combinational therapy.