Understanding and overcoming limitations of vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma
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University of North Carolina at Charlotte
Vesicular stomatitis virus (VSV) is a prototypic nonsegmented negative-strand RNA virus. Lack of preexisting immunity against VSV, inherent oncotropism, and genetic malleability make VSV a widely used platform for vaccine, oncolytic, and gene therapy vectors. VSV proteins and host cellular proteins both determine VSV success as an oncolytic therapy. This dissertation focuses on two host proteins in pancreatic ductal adenocarcinoma (PDAC) that may affect VSV oncolytic efficacy: human Mucin 1 (MUC1) and tumor suppressor TP53 (p53). As MUC1 is known to inhibit other viruses, we tested VSV against murine PDAC cell lines expressing human MUC1 or MUC1-null, and found that VSV demonstrates significant oncolytic ability independent of MUC1 expression status in vitro and in vivo. Importantly, we tested VSV against murine PDAC xenografts for the first time in immunocompetent mice. In vivo VSV treatment resulted in significant reduction of tumor growth for tested mouse PDAC xenografts (+MUC1 or MUC1 null), although the antitumor effect was transient. The antitumor effect was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. Another approach to improve oncolytic therapy is to engineer VSV to express anticancer genes. We generated rVSV encoding a chimeric human p53 that evades inhibition by cellular dominant-negative mutant p53 and confirmed that virus-encoded p53 is functional in cancer cells. As p53 is known to enhance antiviral responses in nonmalignant cells, it was important to determine if the transgene would attenuate VSV in PDACs. Surprisingly, our analysis of global gene expression in infected PDAC cells suggests that the p53 transgene inhibits, rather than attenuates, antiviral responses in cancer cells thereby making the virus a viable option for therapeutic use. In agreement with this, the oncolytic efficacy of VSV expressing p53 against 11 human PDAC cell lines in vitro was not attenuated compared to the parental strain in all cell lines.
Dreau, DidierMarriott, IanRichardson, ChristineWeller, Jennifer
Thesis (Ph.D.)--University of North Carolina at Charlotte, 2014.
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