Abstract 600: The HSV-2 oncolytic virus ΔPK induces multiple death and inflammatory programs associated with inhibition of melanoma tumor growth

Abstract

Abstract Metastatic melanoma is a highly aggressive and drug resistant cancer. Oncolytic virotherapy is a novel therapeutic strategy designed to circumvent cancer resistance through virus replication-induced cancer cell lysis. Unfortunately, its clinical efficacy is modest, apparently related to poor virus replication within the tumors and the failure to stimulate inflammatory/immunotherapeutic pathways. The growth compromised herpes simplex virus type 2 (HSV-2) mutant ΔPK causes metastatic melanoma cell death through activation of multiple non-redundant death pathways. Activation of calpain and caspases-3 and -7 provide the bulk of the death programs, as evidenced by the finding of 80% protection in cells treated with the combination of calpain (PD150606) and pancaspase (zVAD-fmk) inhibitors. In addition, ΔPK upregulates the autophagy proteins Beclin-1 and LC-II and the autophagy inhibitor 3-methyladenine (3-MA) reduces ΔPK-induced cell death by 15-17%. Cell death is further decreased (to a total of 28-34%) by treatment with 3-MA together with the JNK inhibitor SP600125, indicating that JNK signaling and autophagy contribute independently to ΔPK-induced cell death. Inflammatory-related pathways contribute to ΔPK-induced melanoma cell death, as evidenced by caspase-1 activation, interleukin (IL)-1β release into the conditioned medium and upregulation of pro-apoptotic/stress signaling molecules and pro-inflammatory cytokines and chemokines identified by microarray analysis. These include BAD, BIK, BOK, NLRC4, CIDEB, IL-1β, IL-6, IL-8, IL-12α, IL-12β, LTα, CXCL-10, c-JUN and caspases-4, -5, -6, -8, and -10. Tumor burden is significantly reduced by intratumoral injection of ΔPK and xenografts generated from a fresh clinical isolate, were completely eliminated for a period of 1 year following treatment. Growth inhibition is associated with activation of calpain and caspases-3, -7 and -1 and expression of the inflammatory cytokine TNF-α. Collectively, the data indicate that ΔPK eliminates tumor burden through the simultaneous activation of multiple non-redundant death programs and pro-inflammatory signaling, providing a distinct and promising virotherapeutic approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 600. doi:10.1158/1538-7445.AM2011-600