Abstract 3377: Oncolytic herpes simplex virus treatment of malignant peripheral nerve sheath tumor (MPNST) cancer stem-like cell orthotopic tumor model

Abstract

Abstract Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas arising in peripheral nerves that often occur in patients with neurofibromatosis type 1 (NF1) and have an extremely poor prognosis. Therapy consists of surgery followed by radiation and/or chemotherapy, which are generally of limited efficacy. Cancer stem cells are a subpopulation of tumor cells with stem cell like properties that are thought to be important in tumor progression, resistance to therapy, and metastasis. We have isolated MPNST cancer stem-like cells (MSLCs) from a human MPNST cell line by non-adherent sphere-culture in neurosphere media with EGF and bFGF (without serum). Implantation of the MSLCs in the sciatic nerve generates an orthotopic MPNST model in athymic mice. As the tumors grow, mice develop neurologic deficits that are quantified using a neurologic scoring system and externally measurable masses. As a novel therapeutic strategy we are using oncolytic herpes simplex virus (oHSV) vectors, which replicate in and kill tumor cells but not normal tissue. Tumor selectivity is engendered by mutating viral genes that make virus replication non-permissive in ‘normal’ cells, while retaining permissivity in cancer cells. For these studies, we used G47α, a multi-mutated oHSV with deletions in the α34.5 and ICP47 genes and an inactivating LacZ insertion in the ICP6 gene. G47α is very efficacious in many tumor models and is currently in clinical trial for glioblastoma. G47α was able to infect and spread in MSLCs in vitro and MSLC-derived tumors in vivo. Treatment of established MSLC-derived sciatic nerve tumors with a single intratumoral injection of G47α significantly prolonged survival of mice and reduced neurologic deficits. There was no difference in survival between mice treated with 2 x 10^5 pfu versus 2 x 10^6 pfu, although the mice receiving the higher virus dose had significantly higher neurologic score (less deficit). We describe a new preclinical MPNST model generated by implantation of human MSLCs into the sciatic nerve of immune-deficient mice. Treatment of established tumors by oHSV G47α is highly efficacious. These preclinical studies suggest that oHSV should be considered for the treatment of patients with MPNST. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3377. doi:1538-7445.AM2012-3377