Abstract 1383: The effect of a novel angiogenesis inhibitor (TM) on the efficacy of HSV-1 oncolytic virus

Abstract

Abstract Oncolytic viruses (OVs) are modified viruses specifically designed to lyse cancerous cells while leaving surrounding tissue intact. Solid tumors such as glioma represent an excellent candidate for this novel cancer therapy. We are investigating barriers towards oncolytic viral therapy in vivo. The tumor microenvironment plays an inhibitory role in viral propagation and spread. In particular, the angiogenic and inflammatory response that follows OV inoculation have been demonstrated to significantly limit OV efficacy. The goal of our current project is to determine if the novel copper-chelating angiostatic/anti-inflammatory drug, tetrathiomolybdate (TM), represents a potential co-therapy that can be used in conjunction with OV to enhance overall efficacy in a glioma model. Based on previous findings from our laboratory, the anti-cancerous effects of oncolytic viruses can be significantly increased by pre-treatment with an angiostatic agent. Apart from supporting angiogenesis, copper found in serum has also been shown to inhibit wild-type HSV infection and replication. Due it its copper chelating properties, TM has been FDA approved for Wilson's disease and is currently under clinical investigation for efficacy as an angiostatic and antineoplastic agent. Here we tested if copper can inhibit OV mediated glioma cell killing. 1): We found a significant and dose dependant inhibitory effect of copper on the cytotoxic ability of OV against multiple glioma and head and neck SCC cells. 2): The inhibitory effects of copper were apparent even at physiologically relevant concentrations of copper (1 mg/L in serum). 3): Further we found that Cu mediated inhibition of OV killing of glioma cell could be rescued by TM mediated copper chelation. 4): Finally we have tested that TM does not interfere with viral replication or tumor cell killing properties in vitro. Given the potential angiostatic and anti-inflammatory properties of TM, these studies support further in vivo testing of TM in conjunction with oncolytic viral therapy. 5): We are currently testing therapeutic efficacy of combining TM and OV for anti-glioma efficacy in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1383.