Abstract 589: Vascular endothelial growth factor facilitates vaccinia virus tropism and oncolysis in human pancreatic ductal adenocarcinoma

Abstract

Abstract Background: Oncolytic virotherapy is a promising approach to treat cancers resistant to conventional therapies. Vaccinia virus, an enveloped DNA virus from the poxvirus family, has been used as a vector for cancer vaccines and oncolytic viral gene therapy. Wild type vaccinia virus has a natural tropism for cancer cells both in vitro and in vivo due to their increased proliferation, abnormalities in epidermal growth factor and interferon signalling, in addition to other unknown mechanisms. We have recently demonstrated that the anti-tumor efficacy of the Lister strain vaccinia virus, unlike some replicating oncolytic vectors, is not attenuated by hypoxia and even augmented 20 fold in some pancreatic ductal adenocarcinoma (PDAC) cells lines (CT Hiley et al. Gene Therapy 2009. In press). The underlying mechanism is not fully understood. Methods: Vascular Endothelial Growth Factor (VEGF) was detected by an enzyme-linked immunosorbent assay. The effect of VEGF on vaccinia virus infection in human cancer cells was investigated by manipulation of VEGF expression using siRNAs or gene over-expression. Normal human bronchial epithelial cells (NHBE) were used to assess the effect of VEGF on non-transformed cells. Results: Induction of VEGF by hypoxia was found in the supernatants of cancer cell lines showing sensitisation to vaccinia virus under hypoxia. Replication of vaccinia virus was correlated with the level of VEGF expression in a panel of human cancer cell lines. Knockdown of VEGF expression in Suit2 cells by siRNAs reduced transgene expression over 7 fold at 24 and 48 hours post infection (PI) (P<0.05 & P<0.01 respectively) and viral replication 2 fold (P<0.01) at 72 hours PI. Over-expression of VEGF in cell line MiaPaca2, which has a lower level of VEGF expression, enhanced its sensitivity to vaccinia virus. Four fold over-expression of VEGF in MiaPaca2 resulted in levels of only half that seen in Suit2 cells. However a threefold increase in viral replication was observed at 72 hours PI (P<0.01) together with significant increases in transgene expression at 24 and 48 hours and a 40% increase in cytotoxicity at 6 days PI (p<0.05) compared to control. No similar effect on vaccinia virus tropism was seen in NHBE cells at levels of VEGF expression seen in PDAC cell lines. VEGF also augmented vaccinia virus tumour targeting in vivo after systemic administration (P<0.01 at 60 hours post intravenous injection). Conclusion: This novel finding suggests that VEGF expression by cancer cells is at least partly responsible for some of the tumour tropism of wild type Lister vaccinia virus and highlights its suitability for use in poor prognosis tumour types, notably those with high levels of hypoxia and VEGF expression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 589.