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

• Published in: Cancers 2021-03, Vol.13 (5), p.1171
• Main Authors: Holbrook, Molly C, Goad, Dakota W, Grdzelishvili, Valery Z
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Apoptosis; Cancer therapies; Cell cycle; Cell growth; Chemotherapy; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; Directed evolution; DNA; Enzymes; Extracellular matrix; Fibroblasts; Gene therapy; Glucose; Hypoxia; Immunotherapy; Insulin; Insulin-like growth factors; Interferon; Janus kinase; Kinases; Malignancy; Metabolism; Metastasis; Mutation; Oncolysis; p53 Protein; Paclitaxel; Pancreas; Pancreatic cancer; Polycations; Proteins; Recombinants; Replication; Review; Stomatitis; Transgenes; Tumor cells; Tumors; Virus attachment; Viruses
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13051171

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.