Abstract 2714: Vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma

Oncolytic virus (OV) therapy is an anticancer approach that utilizes replication-competent viruses to specifically kill tumor cells. Such selectivity is possible because many tumors are characterized by defective innate immune responses which facilitate selective replication of viruses in cancer cells. As a result, OV can infect, replicate within and kill tumor cells. Successful virus replication in cancer cells leads to the release of newly formed infectious virus particles that go on to infect neighboring tumor cells. Vesicular stomatitis virus (VSV) is a promising OV and has demonstrated preclinical success against a variety of malignancies, however, VSV oncolytic potential has never been studied in pancreatic cancer. About 95% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDA) which are highly invasive with aggressive local growth and rapid metastases to surrounding tissues. PDA is considered one of the most lethal abdominal malignancies with annual deaths closely matching the annual incidence of the disease. Chemotherapy is the primary treatment available; however, patients exhibit little improvement or develop chemoresistance. Therefore, development of new treatment strategies for patients suffering from PDA is of utmost importance. There are several advantages of using VSV as an anticancer therapy. VSV is a prototypic negative-strand RNA virus (family Rhabdoviridae), and its basic biology and interactions with host immune responses have been extensively studied. While VSV is sensitive to IFN-mediated antiviral responses (and therefore unable to productively infect healthy cells), it can specifically infect and kill tumor cells, the majority of which are believed to be defective in Type I IFN production and responses. In addition to tumor specificity, VSV has several important advantages as an OV: (i) replication occurs in the cytoplasm of host cells with no risk of host cell transformation, (ii) cellular uptake in many mammalian cell types occurs rapidly with no cell cycle dependency, (iii) the genome is easily manipulated for enhancement of oncolysis and specificity, and (iv) there is no preexisting immunity against VSV in humans. In this study, the oncolytic potential of VSV was analyzed in a panel of 13 clinically relevant human PDA cell lines and compared to other OV. VSV showed superior oncolytic abilities compared to all other viruses tested, and was effective in killing the majority of tested PDA cell lines. However, we identified some PDA cell lines that showed resistance to oncolysis by all tested viruses. These results were confirmed for several PDA cell lines in nude mice. We also conducted initial analysis of PDA resistance to virus-induced cell death. Our in vitro and in vivo results demonstrate that VSV has good potential as an OV against PDA, while further studies are needed to better understand the molecular mechanisms of resistance of some PDA cell lines to virotherapy. 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 2714. doi:1538-7445.AM2012-2714