Abstract 2488: Reovirus (Reolysin) as a potential therapy for malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma which may occur sporadically in the general population or in association with neurofibromatosis type 1 (NF1), and are highly aggressive and often fatal. NF1 patients are at a greater risk for the development of malignant peripheral nerve sheath tumors than the general population. Current therapy relies upon surgical resection with adjuvant chemotherapy and/or radiotherapy. Clinical trials using Reolysin (Respiratory Enteric Orphan Virus) which is developed from the naturally-occurring human reovirus have demonstrated the efficacy of this reovirus as an oncolytic virotherapy. Reolysin selectively replicates in cancer cells with activated Ras (Ras-GTP), resulting in virus-mediated apoptotic cell death. Hence Reolysin demonstrates promising anticancer activity and has minimal toxicity in patients. Since MPNST is associated with neurofibromin (NF1) deficiency and active Ras we tested these tumors as therapeutic targets for Reolysin treatment using two NF1 deficient human MPNST-derived cell lines (CRL-2884, ST8814) with activated Ras and one sporadic MPNST cell line (STS26T) which expresses NF1 but not active Ras. These were compared with normal human Schwann cells (NHSC) which do not show active Ras and mammary gland cells derived from an NF1 patient (CRL-7329). Reolysin inhibited the proliferation and viability of the three MPNST cell lines at a dose of 0.1 to 10 virus particles/cell, including sporadic MPNST cells which do not have active Ras. In contrast, the NHSC and CRL-7329 cells were more resistant to viral treatment, with apoptosis induced at higher viral concentrations (10,000 and 100,000 virus particles/cell respectively). Furthermore, we examined the effects of Reolysin on the Ras-signaling pathway in a bladder cancer cell line (HTB-4) expressing NF1 and Ras and found that virus induced cytotoxicity was similar to the control cell lines (100,000 virus particles/cell). This study shows that MPNST-derived cell lines including sporadic MPNST without active Ras were efficiently transduced, promoted virus replication and were killed by the oncolytic reovirus. In contrast to the highly sensitive MPNST cell lines, NHSC, CRL-7329 and HTB-4 cells were resistant at similar viral concentrations. Our data suggests the use of oncolytic Reolysin may represent a novel treatment approach for patients with MPNST and provides the basis for preclinical testing of the antitumor effects. Therapeutic efficacy of Reolysin in a mouse model for MPNST is underway. 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 2488. doi:1538-7445.AM2012-2488