Preclinical evaluation of sequential combination of oncolytic adenovirus delta-24-RGD and phosphatidylserine-targeting antibody in pancreatic ductal adenocarcinoma

Bingbing Dai, David Roife, Ya'An Kang, Joy Gumin, Mayrim V.Rios Perez, Xinqun Li, Michael Pratt, Rolf A. Brekken, Juan Fueyo-Margareto, Frederick F. Lang, Jason B. Fleming

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 (P < 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity (P < 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.

Original languageEnglish (US)
Pages (from-to)662-670
Number of pages9
JournalMolecular Cancer Therapeutics
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2017

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Phosphatidylserines
Adenoviridae
Adenocarcinoma
Antibodies
Autophagy
Pancreatic Neoplasms
Oncolytic Viruses
Cell Line
Acridine Orange
Clinical Trials, Phase I
Cyclin D1
Brain Neoplasms
Methylation
Neoplasms
Western Blotting
Apoptosis
Staining and Labeling
Safety
Liver
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Preclinical evaluation of sequential combination of oncolytic adenovirus delta-24-RGD and phosphatidylserine-targeting antibody in pancreatic ductal adenocarcinoma. / Dai, Bingbing; Roife, David; Kang, Ya'An; Gumin, Joy; Perez, Mayrim V.Rios; Li, Xinqun; Pratt, Michael; Brekken, Rolf A.; Fueyo-Margareto, Juan; Lang, Frederick F.; Fleming, Jason B.

In: Molecular Cancer Therapeutics, Vol. 16, No. 4, 01.04.2017, p. 662-670.

Research output: Contribution to journalArticle

Dai, Bingbing ; Roife, David ; Kang, Ya'An ; Gumin, Joy ; Perez, Mayrim V.Rios ; Li, Xinqun ; Pratt, Michael ; Brekken, Rolf A. ; Fueyo-Margareto, Juan ; Lang, Frederick F. ; Fleming, Jason B. / Preclinical evaluation of sequential combination of oncolytic adenovirus delta-24-RGD and phosphatidylserine-targeting antibody in pancreatic ductal adenocarcinoma. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 4. pp. 662-670.
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AU - Gumin, Joy

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AU - Li, Xinqun

AU - Pratt, Michael

AU - Brekken, Rolf A.

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AU - Fleming, Jason B.

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