Oncolytic virotherapy (OV) using modified Herpes simplex virus (HSV) type 1, is currently being evaluated for safety and efficacy in numerous phase I-III clinical trials. However, the host innate immune response and a compromised ability to counter cellular defense responses in order to sustain efficient viral replication in tumor cells is still a major obstacle to efficacious virotherapy. Sodium valporate (VPA) is a simple branched-chain fatty acid FDA-approved medication used in treating epilepsy. We previously demonstrated that pretreatment of cultured glioma cells with VPA significantly increases OV replication. However, the mechanism underlying VPA mediated increased virus replication has not been fully elucidated. Understanding the mechanism of this effect can lead to the development of better pharmacologic sensitizers for OV therapy. We found that activation of STAT3 and inhibition of DNA methylation are involved in VPA's ability to enhance virus replication. Furthermore, we demonstrated that the combination of a DNA methylation inhibitor, 5-Azacitydine (5-Aza), at a 1-2 uM concentration coupled with IL-6-mediated (10ng/mL) STAT3 activation effectively enhanced OV replication 125 fold when compared with OV alone. This combination was comparable to what was previously observed when VPA alone was utilized to increase OV replication. The combination also showed increased anti-glioma activity (ED50 of 5-Aza: 2 uM; with IL-6, 0.3 uM) when compared to only VPA treatment. Given these in vitro results, we are currently performing experiments in mice assessing the effect of 5-Aza pretreatment on enhancing OV therapy of gliomas. Oncolytic HSV in combination with the DNA methylation inhibitor, 5-Aza, and activation of STAT3 represents a promising strategy for treating human gliomas.

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 4080. doi:1538-7445.AM2012-4080