Understanding and overcoming limitations of vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma

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Hastie, E. (2014). Understanding and overcoming limitations of vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

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.

Details
Author

Hastie, Eric

Title

Understanding and overcoming limitations of vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma

Physical Description

1 online resource (149 pages) : PDF

Date

2014

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

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.

Genre

doctoral dissertations

Subjects--Topics

Virology
Biology

Degree

Ph.D.

Keywords

Cancer
Oncolytic
Pancreatic
VSV

Subject Area

Biology

Advisor(s)

Grdzelishvili, Valery

Committee Members

Dreau, Didier
Marriott, Ian
Richardson, Christine
Weller, Jennifer

Degree Note

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2014.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

Hastie_uncc_0694D_10675

Permalink

http://hdl.handle.net/20.500.13093/etd:963