*Review* **Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions**

**Molly C. Holbrook, Dakota W. Goad and Valery Z. Grdzelishvili \***

Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA; mpenton@uncc.edu (M.C.H.); dgoad@uncc.edu (D.W.G.)

**\*** Correspondence: vzgrdzel@uncc.edu

**Simple Summary:** Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a poor prognosis and a dismal survival rate. Oncolytic virus (OV) is an anticancer approach that utilizes replication-competent viruses to preferentially infect and kill tumor cells. Vesicular stomatitis virus (VSV), one such OV, is already in several phase I clinical trials against different malignancies. VSVbased recombinant viruses are effective OVs against a majority of tested PDAC cell lines. However, some PDAC cell lines are resistant to VSV. This review discusses multiple mechanisms responsible for the resistance of some PDACs to VSV-based OV therapy, as well multiple rational approaches to enhance permissiveness of PDACs to VSV and expand the spectrum of PDACs responsive to VSV-based oncolytic virotherapy.

**Abstract:** Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis and a dismal survival rate, expected to become the second leading cause of cancer-related deaths in the United States. Oncolytic virus (OV) is an anticancer approach that utilizes replication-competent viruses to preferentially infect and kill tumor cells. Vesicular stomatitis virus (VSV), one such OV, is already in several phase I clinical trials against different malignancies. VSV-based recombinant viruses are effective OVs against a majority of tested PDAC cell lines. However, some PDAC cell lines are resistant to VSV. Upregulated type I IFN signaling and constitutive expression of a subset of interferon-simulated genes (ISGs) play a major role in such resistance, while other mechanisms, such as inefficient viral attachment and resistance to VSV-mediated apoptosis, also play a role in some PDACs. Several alternative approaches have been shown to break the resistance of PDACs to VSV without compromising VSV oncoselectivity, including (i) combinations of VSV with JAK1/2 inhibitors (such as ruxolitinib); (ii) triple combinations of VSV with ruxolitinib and polycations improving both VSV replication and attachment; (iii) combinations of VSV with chemotherapeutic drugs (such as paclitaxel) arresting cells in the G2/M phase; (iv) arming VSV with p53 transgenes; (v) directed evolution approach producing more effective OVs. The latter study demonstrated impressive long-term genomic stability of complex VSV recombinants encoding large transgenes, supporting further clinical development of VSV as safe therapeutics for PDAC.

**Keywords:** oncolytic virus; virotherapy; pancreatic cancer; pancreatic ductal adenocarcinoma; vesicular stomatitis virus
