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Gene therapy for castration-resistant prostate cancer cells using JC polyomavirus-like particles packaged with a PSA promoter driven-suicide gene


Prostate cancer is the second most common cancer in men globally. Prostate cancer patients at advanced stages are usually treated with androgen deprivation therapy (ADT). However, with disease progression, it often becomes the incurable castration-resistant prostate cancer (CRPC). JC polyomavirus (JCPyV) is a human DNA virus. Its virus-like particles (VLPs) exhibit similar tropism to native virions and they are capable of delivering exogenous genes to the target cells for expression. JCPyV has been detected in prostate cells; therefore, prostate cancer cells may be susceptible to JCPyV infection and JCPyV VLPs may be used as a vector for gene therapy against prostate cancer. Here we constructed a plasmid (pPSAtk) that allows expression of the thymidine kinase suicide gene only in androgen receptor (AR) positive prostate cancer cells using the prostate-specific antigen (PSA) promoter, and used JCPyV VLPs as a vector to carry pPSAtk (PSAtk-VLPs) for transcriptional targeting in prostate cancer cells. In this study, we found that PSAtk-VLPs could only kill AR-positive CRPC 22Rv1 cells in vitro and inhibit the growth of tumor nodules in the xenograft mouse model. Our results reveal that PSAtk-VLPs could potentially be used as a new option for treating CRPC patients in the future.

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  1. 1.

    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

  3. 3.

    Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.

  4. 4.

    Nguyen PL, Alibhai SM, Basaria S, D’Amico AV, Kantoff PW, Keating NL, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825–36.

  5. 5.

    Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;351:1488–90.

  6. 6.

    Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.

  7. 7.

    Buttigliero C, Tucci M, Bertaglia V, Vignani F, Bironzo P, Di Maio M, et al. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev. 2015;41:884–92.

  8. 8.

    Naldini L. Gene therapy returns to centre stage. Nature. 2015;526:351–60.

  9. 9.

    Goldmann C, Petry H, Frye S, Ast O, Ebitsch S, Jentsch KD, et al. Molecular cloning and expression of major structural protein VP1 of the human polyomavirus JC virus: formation of virus-like particles useful for immunological and therapeutic studies. J Virol. 1999;73:4465–9.

  10. 10.

    Ou WC, Wang M, Fung CY, Tsai RT, Chao PC, Hseu TH, et al. The major capsid protein, VP1, of human JC virus expressed in Escherichia coli is able to self-assemble into a capsid-like particle and deliver exogenous DNA into human kidney cells. J Gen Virol. 1999;80(Pt 1):39–46.

  11. 11.

    Chao CN, Huang YL, Lin MC, Fang CY, Shen CH, Chen PL, et al. Inhibition of human diffuse large B-cell lymphoma growth by JC polyomavirus-like particles delivering a suicide gene. J Transl Med. 2015;13:29.

  12. 12.

    Fang CY, Tsai YD, Lin MC, Wang M, Chen PL, Chao CN, et al. Inhibition of human bladder cancer growth by a suicide gene delivered by JC polyomavirus virus-like particles in a mouse model. J Urol. 2015;193:2100–6.

  13. 13.

    Chao CN, Lin MC, Fang CY, Chen PL, Chang D, Shen CH, et al. Gene therapy for human lung adenocarcinoma using a suicide gene driven by a lung-specific promoter delivered by JC virus-like particles. PLoS One. 2016;11:e0157865.

  14. 14.

    Chao CN, Yang YH, Wu MS, Chou MC, Fang CY, Lin MC, et al. Gene therapy for human glioblastoma using neurotropic JC virus-like particles as a gene delivery vector. Sci Rep. 2018;8:2213.

  15. 15.

    Delbue S, Matei DV, Carloni C, Pecchenini V, Carluccio S, Villani S, et al. Evidence supporting the association of polyomavirus BK genome with prostate cancer. Med Microbiol Immunol. 2013;202:425–30.

  16. 16.

    Anzivino E, Rodio DM, Mischitelli M, Bellizzi A, Sciarra A, Salciccia S, et al. High frequency of JCV DNA detection in prostate cancer tissues. Cancer Genom Proteom. 2015;12:189–200.

  17. 17.

    Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008;8:268–78.

  18. 18.

    Pang S, Taneja S, Dardashti K, Cohan P, Kaboo R, Sokoloff M, et al. Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer. Hum Gene Ther. 1995;6:1417–26.

  19. 19.

    Fang CY, Lin PY, Ou WC, Chen PL, Shen CH, Chang D, et al. Analysis of the size of DNA packaged by the human JC virus-like particle. J Virol Methods. 2012;182:87–92.

  20. 20.

    Latham JP, Searle PF, Mautner V, James ND. Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer: construction and testing of a tissue-specific adenovirus vector. Cancer Res. 2000;60:334–41.

  21. 21.

    Karjoo Z, Chen X, Hatefi A. Progress and problems with the use of suicide genes for targeted cancer therapy. Adv Drug Deliv Rev. 2016;99(Pt A):113–28.

  22. 22.

    Schoenborn JR, Nelson P, Fang M. Genomic profiling defines subtypes of prostate cancer with the potential for therapeutic stratification. Clin Cancer Res. 2013;19:4058–66.

  23. 23.

    Mills IG. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer. Nat Rev Cancer. 2014;14:187–98.

  24. 24.

    Riegman PH, Vlietstra RJ, van der Korput JA, Brinkmann AO, Trapman J. The promoter of the prostate-specific antigen gene contains a functional androgen responsive element. Mol Endocrinol. 1991;5:1921–30.

  25. 25.

    Ma Y, Luk A, Young FP, Lynch D, Chua W, Balakrishnar B, et al. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies. Int J Mol Sci. 2016;17.

  26. 26.

    DeCaprio JA, Garcea RL. A cornucopia of human polyomaviruses. Nat Rev Microbiol. 2013;11:264–76.

  27. 27.

    Chen LS, Wang M, Ou WC, Fung CY, Chen PL, Chang CF, et al. Efficient gene transfer using the human JC virus-like particle that inhibits human colon adenocarcinoma growth in a nude mouse model. Gene Ther. 2010;17:1033–41.

  28. 28.

    Lin MC, Wang M, Fang CY, Chen PL, Shen CH, Chang D. Inhibition of BK virus replication in human kidney cells by BK virus large tumor antigen-specific shRNA delivered by JC virus-like particles. Antivir Res. 2014;103:25–31.

  29. 29.

    Chang CF, Wang M, Ou WC, Chen PL, Shen CH, Lin PY, et al. Human JC virus-like particles as a gene delivery vector. Expert Opin Biol Ther. 2011;11:1169–75.

  30. 30.

    Yoshimura I, Ikegami S, Suzuki S, Tadakuma T, Hayakawa M. Adenovirus mediated prostate specific enzyme prodrug gene therapy using prostate specific antigen promoter enhanced by the Cre-loxP system. J Urol. 2002;168:2659–64.

  31. 31.

    Yu D, Chen D, Chiu C, Razmazma B, Chow YH, Pang S. Prostate-specific targeting using PSA promoter-based lentiviral vectors. Cancer Gene Ther. 2001;8:628–35.

  32. 32.

    Ibraheem D, Elaissari A, Fessi H. Gene therapy and DNA delivery systems. Int J Pharm. 2014;459:70–83.

  33. 33.

    Teunissen EA, de Raad M, Mastrobattista E. Production and biomedical applications of virus-like particles derived from polyomaviruses. J Control Release. 2013;172:305–21.

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This research was supported by the Ministry of Science and Technology [grant number MOST 106-2320-B-194-002-MY3], Taiwan; and through Ditmanson Medical Foundation Chiayi Christian Hospital [grant number R104-023].

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Correspondence to Deching Chang or Cheng-Huang Shen.

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