**1. Introduction**

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic neoplasm. It is a highly invasive malignancy, which forms a stromal desmoplastic reaction (desmoplasia), characterized by a dramatic increase in the proliferation of alpha-smooth muscle actin-positive fibroblasts and an increased production of many extracellular matrix components [1]. Family history, diabetes, and smoking are the most well-established risk factors for developing pancreatic cancer. Despite being only the 13th most common type

**Citation:** Holbrook, M.C.; Goad, D.W.; Grdzelishvili, V.Z. Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions. *Cancers* **2021**, *13*, 1171. https://doi.org/ 10.3390/cancers13051171

Academic Editors: Antonio Marchini, Carolina S. Ilkow and Alan Melcher

Received: 1 February 2021 Accepted: 5 March 2021 Published: 9 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

of cancer, PDAC is the fourth-leading cause of cancer-related deaths and is predicted to become the second-leading cause of cancer-related death by 2030, as incidence increases while rates of survivorship remain stagnant due to late diagnosis and limited treatment options [2].

*KRAS*, *CDKN2A*, *TP53*, and *SMAD4* serve as driver genes for PDAC development, and the vast majority of patients with fully established pancreatic cancer carry genetic defects in at least one of these genes [3]. Mutations in KRAS are present in 90% of PDAC tumors, 95% of PDAC tumors have mutations in *CDKN2A* (encodes p16), 50–75% in *TP53*, and *SMAD4* (*DPC4*) is lost in approximately 50% of PDAC tumors [4]. Mutated *KRAS* oncogene leads to an abnormal, constitutively active, Ras protein. This results in aberrant activation of pathways responsible for survival and proliferation [5]. Inactivation of the tumor suppressor gene *CDKN2A* results in the loss of p16, a protein that serves as a regulator of the G1-S checkpoint of the cell cycle. Abnormalities in *TP53* prevent it from acting as a tumor suppressor protein, including its important role as a regulator of DNA-damage checkpoints. Furthermore, many p53 mutants acquire devastating gain-of-function oncogenic activities, actually promoting cell survival, proliferation, invasion, migration, chemoresistance, and chronic inflammation. *SMAD4* (*DPC4*) is related to the TGF-β signaling pathway, but some mutations result in abnormal signaling by TGF-β, a transforming growth factor receptor on the cell surface which can further increase the risk of cancer development by increasing the rate of cell growth and replication. In addition, germline mutations within BRCA2, BRCA1, ATM, and other genes were frequently identified in PDACs as inherited traits increasing susceptibility to PDAC development later in life [6,7]. These genes, especially when identified as being comorbid, are correlated with a significantly higher metastatic burden [8–10].

The primary treatments for PDAC include surgery, chemotherapy, radiotherapy, and palliative care [11]. Surgical resection still retains the greatest chance of success for potentially curing PDAC, however late-stage diagnosis due to ambiguous symptoms often results in tumors that are too-far progressed for surgery alone. Less than 25% of patients that present with PDAC are eligible for surgical resection, and 5-year survivorship of completely resected patients is approximately 37% [4]. In addition, even in patients where surgical resection was performed with either preparatory or subsequent adjuvant chemotherapy, there is a high rate of recurrence, and up to 80% of patients with recurrent PDAC will relapse with local and/or distant disease, which is associated with mortality within 2 years from diagnosis.

Recent advances in the understanding of the molecular biology, diagnosis, and staging of PDAC will hopefully lead to greater progress in the development of novel treatment approaches for PDAC patients. One such approach is oncolytic virus (OV) therapy, which utilizes replication-competent viruses to preferentially infect, replicate in, and kill cancer cells. In this review, we will discuss current advances with OV therapy for PDAC, with a special focus on vesicular stomatitis virus (VSV), the major interest of our laboratory. For comprehensive reviews of gene therapy for pancreatic cancer (unlike oncolytic virotherapy, gene therapy is typically based on replication-defective viral vectors for transgene delivery), we refer to these excellent papers [12,13].
