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:

Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer

Cancer Gene Therapy volume 20, pages 394–402 (2013)Cite this article

Subjects

Abstract

Conditionally replicating adenoviruses (CRAds) utilize tissue-specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer (PCa) gene therapy require androgens to activate prostate-specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen-suppressive therapy. We describe a novel prostate-specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A and AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and nonsteroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR-responsive genes and E1A-responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens and a particularly attractive adjuvant strategy for intensity-modulated radiation therapy of high-risk PCas.

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Petrylak DP . Chemotherapy for advanced hormone refractory prostate cancer. Urology 1999; 54: 30–35.

    Article  CAS  Google Scholar 

  2. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–1520.

    Article  CAS  Google Scholar 

  3. Kantoff P . Recent progress in management of advanced prostate cancer. Oncology 2005; 19: 631–636.

    PubMed  Google Scholar 

  4. Berges RR, Vukanovic J, Epstein JI, CarMichel M, Cisek L, Johnson DE et al. Implication of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1995; 1: 473–480.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Visakorpi T, Kallioniemi OP, Paronen IY, Isola JJ, Heikkinen AI, Koivula TA . Flow cytometric analysis of DNA ploidy and S-phase fraction from prostatic carcinomas: implications for prognosis and response to endocrine therapy. Br J Cancer 1991; 64: 578–582.

    Article  CAS  Google Scholar 

  6. Spindler KR, Eng CY, Berk AJ . An adenovirus early region 1A protein is required for maximal viral DNA replication in growth-arrested human cells. J Virol 1985; 53: 742–750.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Greber UF, Willetts M, Webster P, Helenius A . Stepwise dismantling of adenovirus 2 during entry into cells. Cell 1993; 75: 477–486.

    Article  CAS  Google Scholar 

  8. Gurnani M, Lipari P, Dell J, Shi B, Nielsen LL . Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer. Cancer Chemother Pharmacol 1999; 44: 143–151.

    Article  CAS  Google Scholar 

  9. Shalev M, Kadmon D, Teh BS, Butler EB, Aguilar-Cordova E, Thompson TC et al. Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer. J Urol 2000; 163: 1747–1750.

    Article  CAS  Google Scholar 

  10. Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62: 4968–4976.

    CAS  PubMed  Google Scholar 

  11. Small EJ, Carducci MA, Burke JM, Rodriguez R, Fong L, van Ummersen L et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther 2006; 14: 107–117.

    Article  CAS  Google Scholar 

  12. DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001; 61: 7464–7472.

    CAS  Google Scholar 

  13. Hoti N, Li Y, Chen CL, Chowdhury WH, Johns DC, Xia Q et al. Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses. Mol Ther 2007; 15: 1495–1503.

    Article  Google Scholar 

  14. D'Amico AV, Schultz D, Loffredo M, Dugal R, Hurwitz M, Kaplan I et al. Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 284: 1280–1283 2000.

    Article  CAS  Google Scholar 

  15. Zapatero A, Garcia-Vicente F, Martin de Vidales C, Cruz Conde A, Ibanez Y, Fernandez I et al. Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease? Int J Radiat Oncol Biol Phys 2011; 81: 1279–1285.

    Article  CAS  Google Scholar 

  16. Ceraline J, Erdmann E, Erbs P, Deslandres-Cruchant M, Jacqmin D, Duclos B et al. A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer. Eur J Endocrinol 2003; 148: 99–110.

    Article  CAS  Google Scholar 

  17. van der Poel HG, McCadden J, Verhaegh GW, Kruszewski M, Ferrer F, Schalken JA et al. A novel method for the determination of basal gene expression of tissue-specific promoters: an analysis of prostate-specific promoters. Cancer Gene Ther 2001; 8: 927–935.

    Article  CAS  Google Scholar 

  18. Liu C, Zhang Y, Liu MM, Zhou H, Chowdhury W, Lupold SE et al. Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate cancer. Int J Radiat Biol 2010; 86: 220–229.

    Article  CAS  Google Scholar 

  19. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.

    CAS  PubMed  Google Scholar 

  20. Ryan CJ, Small EJ . The selection of hormonal therapy in prostate cancer: who, when, and for how long? J Natl Compr Canc Netw 2004; 2: 261–268.

    Article  Google Scholar 

  21. Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW . Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer 1994; 57: 406–412.

    Article  CAS  Google Scholar 

  22. Reich NC, Sarnow P, Duprey E, Levine AJ . Monoclonal antibodies which recognize native and denatured forms of the adenovirus DNA-binding protein. Virology 1983; 128: 480–484.

    Article  CAS  Google Scholar 

  23. Hoti N, Chowdhury WH, Mustafa S, Ribas J, Castanares M, Johnson T et al. Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses. Cancer Gene Ther 2010; 17: 585–597.

    Article  CAS  Google Scholar 

  24. Bolla M, Fourneret P, Beneyton V, Tessier A, Jover F, Verry C . [Combination of external irradiation and androgen suppression for prostate cancer: facts and questions]. Cancer Radiother 2010; 14: 510–514.

    Article  CAS  Google Scholar 

  25. Han G, Buchanan G, Ittmann M, Harris JM, Yu X, Demayo FJ et al. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci USA 2005; 102: 1151–1156.

    Article  CAS  Google Scholar 

  26. Waltering KK, Urbanucci A, Visakorpi T . Androgen receptor (AR) aberrations in castration-resistant prostate cancer. Mol Cell Endocrinol 2012; 360: 38–43.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by grants from Flight Attendant Medical Research Institute (FAMRI) to Naser Uddin Hoti, and by the PCW and RO1 (R01CA121153-01A2) award to Ronald Rodriguez.

Author information

Author notes

  1. T J Johnson, N Höti and C Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. James Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    T J Johnson, N Höti, C Liu, W H Chowdhury, Y Li, S E Lupold & R Rodriguez

  2. Departments of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins Medical Institute, Baltimore, MD, USA

    Y Zhang, S E Lupold & T DeWeese

  3. Department of Urology, The University of Texas Health Science Center San Antonio, Texas, USA

    R Rodriguez

Authors
  1. T J Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Höti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W H Chowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S E Lupold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T DeWeese
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Rodriguez.

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

Johnson, T., Höti, N., Liu, C. et al. Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer. Cancer Gene Ther 20, 394–402 (2013). https://doi.org/10.1038/cgt.2013.34

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2013.34

Keywords

This article is cited by

Search

Advanced search

Quick links