Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine

Cancer Gene Therapy volume 18, pages 734–743 (2011)Cite this article

Subjects

Abstract

Pancreatic adenocarcinoma has a poor prognosis and frequently develops resistance to standard chemotherapeutics. Oncolytic adenoviruses represent a promising approach to overcome treatment resistance. The replication-selective dl922–947 adenovirus, defective in pRb binding, targets cancers with deregulated cell cycle control, such as the majority of pancreatic tumors. Cell killing efficacy was higher for dl922–947 than for adenovirus type 5 (Ad5) and the clinically approved dl1520 in pancreatic cancer cells with K-ras, p16 and p53 mutations. Combinations of dl922–947 and 5-fluorouracil or gemcitabine (2′2′-difluoro-2-deoxytidine) resulted in strong synergistic cell killing in Suit-2 and the highly drug- and virus-resistant Hs766T cells. Viral uptake increased in response to drugs, but was independent of the expression levels of the viral attachment receptor coxsackie and adenovirus receptor (CAR), whereas expression levels of the internalization receptors αvβ3- and αvβ5-integrins were increased. Early viral E1A expression was potently induced with drugs contributing to the synergistic effects. The dl922–947 mutant was more efficacious than Ad5 in vivo in Hs766T and Suit-2 xenograft models. In combination with gemcitabine, median survival was further prolonged. We demonstrate that dl922–947 is highly efficacious in pancreatic cancers and conclude that oncolytic adenoviruses harboring the E1ACR2 deletion have great potential for development into future clinical candidates for pancreatic cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E . Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277–300.

    Article  PubMed  Google Scholar 

  2. Burris H, Storniolo AM . Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 1997; 33 (Suppl 1): S18–S22.

    Article  CAS  PubMed  Google Scholar 

  3. Huang P, Plunkett W . Fludarabine- and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 1995; 36: 181–188.

    Article  CAS  PubMed  Google Scholar 

  4. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297: 267–277.

    Article  CAS  PubMed  Google Scholar 

  5. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010; 304: 1073–1081.

    Article  CAS  PubMed  Google Scholar 

  6. Chua YJ, Cunningham D . Chemotherapy for advanced pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20: 327–348.

    Article  CAS  PubMed  Google Scholar 

  7. Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 2009; 101: 1658–1663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966.

    Article  CAS  PubMed  Google Scholar 

  9. Parato KA, Senger D, Forsyth PA, Bell JC . Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 2005; 5: 965–976.

    Article  CAS  PubMed  Google Scholar 

  10. Aghi M, Martuza RL . Oncolytic viral therapies—the clinical experience. Oncogene 2005; 24: 7802–7816.

    Article  CAS  PubMed  Google Scholar 

  11. Harada JN, Berk AJ . p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication. J Virol 1999; 73: 5333–5344.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  13. O’Shea CC, Choi S, McCormick F, Stokoe D . Adenovirus overrides cellular checkpoints for protein translation. Cell Cycle 2005; 4: 883–888.

    Article  PubMed  Google Scholar 

  14. O’Shea CC, Johnson L, Bagus B, Choi S, Nicholas C, Shen A et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004; 6: 611–623.

    Article  PubMed  Google Scholar 

  15. Liu TC, Galanis E, Kirn D . Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol 2007; 4: 101–117.

    Article  CAS  PubMed  Google Scholar 

  16. Garber K . China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006; 98: 298–300.

    Article  PubMed  Google Scholar 

  17. Kirn D . Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? Gene Ther 2001; 8: 89–98.

    CAS  PubMed  Google Scholar 

  18. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al. a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–885.

    Article  CAS  PubMed  Google Scholar 

  19. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003; 9: 555–561.

    CAS  PubMed  Google Scholar 

  20. Mulvihill S, Warren R, Venook A, Adler A, Randlev B, Heise C et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Ther 2001; 8: 308–315.

    Article  CAS  PubMed  Google Scholar 

  21. Fulci G, Dmitrieva N, Gianni D, Fontana EJ, Pan X, Lu Y et al. Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses. Cancer Res 2007; 67: 9398–9406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heise C, Hermiston T, Johnson L, Brooks G, Sampson-Johannes A, Williams A et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 2000; 6: 1134–1139.

    Article  CAS  PubMed  Google Scholar 

  23. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000; 19: 2–12.

    Article  CAS  PubMed  Google Scholar 

  24. Page JG, Tian B, Schweikart K, Tomaszewski J, Harris R, Broadt T et al. Identifying the safety profile of a novel infectivity-enhanced conditionally replicative adenovirus, Ad5-delta24-RGD, in anticipation of a phase I trial for recurrent ovarian cancer. Am J Obstet Gynecol 2007; 196: 389; e381-389; discussion e389-310.

    Article  PubMed  Google Scholar 

  25. Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 2001; 439: 798–802.

    Article  CAS  PubMed  Google Scholar 

  26. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997; 57: 3126–3130.

    CAS  PubMed  Google Scholar 

  27. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994; 8: 27–32.

    Article  CAS  PubMed  Google Scholar 

  28. Bazan-Peregrino M, Carlisle RC, Hernandez-Alcoceba R, Iggo R, Homicsko K, Fisher KD et al. Comparison of molecular strategies for breast cancer virotherapy using oncolytic adenovirus. Hum Gene Ther 2008; 19: 873–886.

    Article  CAS  PubMed  Google Scholar 

  29. Libertini S, Iacuzzo I, Ferraro A, Vitale M, Bifulco M, Fusco A et al. Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and its antineoplastic activity against anaplastic thyroid carcinoma cells. Endocrinology 2007; 148: 5186–5194.

    Article  CAS  PubMed  Google Scholar 

  30. Libertini S, Iacuzzo I, Perruolo G, Scala S, Ierano C, Franco R et al. Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922–947. Clin Cancer Res 2008; 14: 6505–6514.

    Article  CAS  PubMed  Google Scholar 

  31. Radhakrishnan S, Miranda E, Ekblad M, Holford A, Pizarro MT, Lemoine NR et al. Efficacy of oncolytic mutants targeting pRb and p53 pathways is synergistically enhanced when combined with cytotoxic drugs in prostate cancer cells and tumor xenografts. Hum Gene Ther 2010; 21: 1311–1325.

    Article  CAS  PubMed  Google Scholar 

  32. Gomez-Manzano C, Alonso MM, Yung WK, McCormick F, Curiel DT, Lang FF et al. Delta-24 increases the expression and activity of topoisomerase I and enhances the antiglioma effect of irinotecan. Clin Cancer Res 2006; 12: 556–562.

    Article  CAS  PubMed  Google Scholar 

  33. Raki M, Kanerva A, Ristimaki A, Desmond RA, Chen DT, Ranki T et al. Combination of gemcitabine and Ad5/3-Delta24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer. Gene Ther 2005; 12: 1198–1205.

    Article  CAS  PubMed  Google Scholar 

  34. Liao Y, Zou YY, Xia WY, Hung MC . Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer. Cancer Gene Ther 2004; 11: 594–602.

    Article  CAS  PubMed  Google Scholar 

  35. Leitner S, Sweeney K, Oberg D, Davies D, Miranda E, Lemoine NR et al. Oncolytic adenoviral mutants with E1B19K gene deletions enhance gemcitabine-induced apoptosis in pancreatic carcinoma cells and anti-tumor efficacy in vivo. Clin Cancer Res 2009; 15: 1730–1740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheong SC, Wang Y, Meng JH, Hill R, Sweeney K, Kirn D et al. E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models. Cancer Gene Ther 2008; 15: 40–50.

    Article  CAS  PubMed  Google Scholar 

  37. Chou TC . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58: 621–681.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, Hallden G, Hill R, Anand A, Liu TC, Francis J et al. E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat Biotechnol 2003; 21: 1328–1335.

    Article  CAS  PubMed  Google Scholar 

  39. Raki M, Sarkioja M, Desmond RA, Chen DT, Butzow R, Hemminki A et al. Oncolytic adenovirus Ad5/3-delta24 and chemotherapy for treatment of orthotopic ovarian cancer. Gynecol Oncol 2008; 108: 166–172.

    Article  CAS  PubMed  Google Scholar 

  40. Öberg D, Yanover E, Sweeney K, Adam V, Costas C, Lemoine NR et al. Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant (AdΔΔ) in prostate and pancreatic cancers. Clin Canc Res 2010; 16: 541–553.

    Article  Google Scholar 

  41. Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE . A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum Mutat 2003; 21: 445.

    Article  PubMed  Google Scholar 

  42. Ryu B, Jones J, Blades NJ, Parmigiani G, Hollingsworth MA, Hruban RH et al. Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res 2002; 62: 819–826.

    CAS  PubMed  Google Scholar 

  43. Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold Jr DP et al. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 1984; 44: 717–726.

    CAS  PubMed  Google Scholar 

  44. Lockley M, Fernandez M, Wang Y, Li NF, Conroy S, Lemoine N et al. Activity of the adenoviral E1A deletion mutant dl922–947 in ovarian cancer: comparison with E1A wild-type viruses, bioluminescence monitoring, and intraperitoneal delivery in icodextrin. Cancer Res 2006; 66: 989–998.

    Article  CAS  PubMed  Google Scholar 

  45. Pearson AS, Koch PE, Atkinson N, Xiong M, Finberg RW, Roth JA et al. Factors limiting adenovirus-mediated gene transfer into human lung and pancreatic cancer cell lines. Clin Cancer Res 1999; 5: 4208–4213.

    CAS  PubMed  Google Scholar 

  46. Blair GE, Dixon SC, Griffiths SA, Zajdel ME . Restricted replication of human adenovirus type 5 in mouse cell lines. Virus Res 1989; 14: 339–346.

    Article  CAS  PubMed  Google Scholar 

  47. Hallden G, Hill R, Wang Y, Anand A, Liu TC, Lemoine NR et al. Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy. Mol Ther 2003; 8: 412–424.

    Article  CAS  PubMed  Google Scholar 

  48. Yu DC, Chen Y, Dilley J, Li Y, Embry M, Zhang H et al. Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Cancer Res 2001; 61: 517–525.

    CAS  PubMed  Google Scholar 

  49. Frisch SM, Mymryk JS . Adenovirus-5 E1A: paradox and paradigm. Nat Rev Mol Cell Biol 2002; 3: 441–452.

    Article  CAS  PubMed  Google Scholar 

  50. Routes JM, Ryan S, Clase A, Miura T, Kuhl A, Potter TA et al. Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL). J Immunol 2000; 165: 4522–4527.

    Article  CAS  PubMed  Google Scholar 

  51. Routes JM, Ryan S, Clase A, Miura T, Kuhl A, Potter TA et al. Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL). J Immunol 2000; 165: 4522–4527.

    Article  CAS  PubMed  Google Scholar 

  52. Madhusudan S, Tamir A, Bates N, Flanagan E, Gore ME, Barton DP et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A–lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene. Clin Cancer Res 2004; 10: 2986–2996.

    Article  CAS  PubMed  Google Scholar 

  53. Hortobagyi GN, Ueno NT, Xia W, Zhang S, Wolf JK, Putnam JB et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J Clin Oncol 2001; 19: 3422–3433.

    Article  CAS  PubMed  Google Scholar 

  54. Yoo GH, Hung MC, Lopez-Berestein G, LaFollette S, Ensley JF, Carey M et al. Phase I trial of intratumoral liposome E1A gene therapy in patients with recurrent breast and head and neck cancer. Clin Cancer Res 2001; 7: 1237–1245.

    CAS  PubMed  Google Scholar 

  55. Lanni JS, Lowe SW, Licitra EJ, Liu JO, Jacks T . 53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci USA 1997; 94: 9679–9683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liao Y, Hung MC . Regulation of the activity of p38 mitogen-activated protein kinase by Akt in cancer and adenoviral protein E1A-mediated sensitization to apoptosis. Mol Cell Biol 2003; 23: 6836–6848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Frisch SM . E1A as a tumor suppressor gene: commentary re S. Madhusudan et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A–lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene. Clin Cancer Res 2004; 10: 2905–290.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by Cancer Research-UK (C633-A6253/A6251 programme grant) and Barts and The London Charity.

Author information

Authors and Affiliations

  1. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

    M Bhattacharyya, J Francis, N R Lemoine & G Halldén

  2. FACS Laboratory, Cancer Research UK, London Research Institute, London, UK

    A Eddouadi

Authors
  1. M Bhattacharyya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Francis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Eddouadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N R Lemoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Halldén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Halldén.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhattacharyya, M., Francis, J., Eddouadi, A. et al. An oncolytic adenovirus defective in pRb-binding (dl922–947) can efficiently eliminate pancreatic cancer cells and tumors in vivo in combination with 5-FU or gemcitabine. Cancer Gene Ther 18, 734–743 (2011). https://doi.org/10.1038/cgt.2011.45

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2011.45

Keywords

Search

Advanced search

Quick links