Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma

• Published in: Molecular cancer therapeutics 2017-04, Vol.16 (4), p.662-670
• Main Authors: Dai, Bingbing, Roife, David, Kang, Ya'an, Gumin, Joy, Rios Perez, Mayrim V, Li, Xinqun, Pratt, Michael, Brekken, Rolf A, Fueyo-Margareto, Juan, Lang, Frederick F, Fleming, Jason B
• Format: Article
• Language: English
• Subjects: Acridine orange; Adenocarcinoma; Adenoviridae; Animals; Anticancer properties; Antitumor activity; Apoptosis; Autophagy; Brain; Brain tumors; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - therapy; Cell Line, Tumor; Cell Survival; Clonal deletion; Cyclin D1; Cyclin D1 - genetics; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cytotoxicity; Dependovirus - physiology; DNA Methylation; E2F protein; Evaluation; Gene deletion; Genetic Therapy - methods; Hepatocytes; Humans; Immune response; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Metastases; Mice; Oncolysis; Oncolytic Viruses - physiology; p16 Protein; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - therapy; Phagocytosis; Phosphatidylserine; Phosphatidylserines - metabolism; Promoter Regions, Genetic; Sequence Deletion; Therapy; Toxicity; Tumor cells; Viruses; Western blotting; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0526

Delta-24-RGD (DNX-2401) is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase I clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high cyclin D1 expression. Induction of autophagy and apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and acridine orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and phosphatidylserine targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control ( < 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity ( < 0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy. .