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Experimental virotherapy of chemoresistant pancreatic carcinoma using infectivity-enhanced fiber-mosaic oncolytic adenovirus

Cancer Gene Therapy volume 21, pages 264–274 (2014)Cite this article

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Abstract

Pancreatic cancer is a significant clinical problem and novel therapeutic approaches are desperately needed. Recent advances in conditionally replicative adenovirus-based (CRAd) oncolytic virus design allow the application of CRAd vectors as a therapeutic strategy to efficiently target and eradicate chemoresistant pancreatic cancer cells, thereby improving the efficacy of pancreatic cancer treatment. The goal of this study was to construct and validate the efficacy of an infectivity-enhanced, liver-untargeted, tumor-specific CRAd vector. A panel of CRAds has been derived that embodies the C-X-C chemokine receptor type 4 promoter for conditional replication, two-fiber complex mosaicism for targeting expansion and hexon hypervariable region 7 (HVR7) modification for liver untargeting. We evaluated CRAds for cancer virotherapy using a human pancreatic tumor xenograft model. Employment of the fiber mosaic approach improved CRAd replication in pancreatic tumor xenografts. Substitution of the HVR7 of the Ad5 hexon for Ad serotype 3 hexon resulted in decreased liver tropism of systemically administrated CRAd. Obtained data demonstrated that employment of complex mosaicism increased efficacy of the combination of oncolytic virotherapy with chemotherapy in a human pancreatic tumor xenograft model.

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Acknowledgements

We thank Cynthia L. Marich from the Biologic Therapeutics Center, Department of Radiation Oncology, School of Medicine, Washington University in St Louis for her assistance in preparing the manuscript. This work was supported in part by the National Institutes of Health under award number 5P50 CA101955.

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Authors and Affiliations

  1. Department of Radiation Oncology, School of Medicine, Washington University in St Louis, St Louis, MO, USA

    S A Kaliberov, L N Kaliberova & D T Curiel

  2. Division of Radiation Biology, Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    D J Buchsbaum

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  1. S A Kaliberov
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  2. L N Kaliberova
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  3. D J Buchsbaum
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  4. D T Curiel
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Correspondence to S A Kaliberov.

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Kaliberov, S., Kaliberova, L., Buchsbaum, D. et al. Experimental virotherapy of chemoresistant pancreatic carcinoma using infectivity-enhanced fiber-mosaic oncolytic adenovirus. Cancer Gene Ther 21, 264–274 (2014). https://doi.org/10.1038/cgt.2014.26

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