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.

  • Review Article
  • Published:

Drug Insight: cancer cell immortality—telomerase as a target for novel cancer gene therapies

Abstract

Rapid advances in our understanding of the molecular basis of cancer development and progression over the past three decades have led to the design of new potential cancer therapies. High throughput target validation and expression studies are expected to yield a powerful arsenal of new cancer treatments, but untangling the complex pathways underlying the major cancer phenotypes remains a significant challenge. A considerable body of evidence in recent years implicates deregulated expression of a single multi-component enzyme, telomerase, as a causative factor at the heart of immortalization in the vast majority of human tumors. This review highlights the potential of telomerase as a target for novel cancer therapies. The potential of exploiting the selectivity of the telomerase family of genes within cancer cells to develop gene therapy strategies is discussed, and the progress towards translating these novel therapeutics from the laboratory to the clinic is reviewed.

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

Access options

Buy this article

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

Figure 1: The products of two genes are required to reconstitute basic telomerase activity; the RNA component, hTR, which includes the template for synthesis of telomere DNA, and the protein catalytic component, hTERT, which has reverse transcriptase activity.
Figure 2: Telomerase-directed molecular therapeutics.
Figure 3: (A) Telomerase-directed gene therapy.

Similar content being viewed by others

References

  1. Keith WN et al. (2001) Telomerase and cancer: time to move from a promising target to a clinical reality. J Pathol 195: 404–414

    Article  CAS  Google Scholar 

  2. Keith WN et al. (2002) Telomerase-directed molecular therapeutics. Expert Rev Mol Med 2002: 1–25

    Google Scholar 

  3. Kim NW et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011–2015

    Article  CAS  Google Scholar 

  4. Masutomi K et al. (2000) Telomerase activity reconstituted in vitro with purified human telomerase reverse transcriptase and human telomerase RNA component. J Biol Chem 275: 22568–22573

    Article  CAS  Google Scholar 

  5. Kim MM et al. (2001) A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Proc Natl Acad Sci USA 98: 7982–7987

    Article  CAS  Google Scholar 

  6. White LK et al. (2001) Telomerase inhibitors. Trends Biotechnol 19: 114–120

    Article  CAS  Google Scholar 

  7. Lavelle F et al. (2000) Telomerase: a therapeutic target for the third millennium? Crit Rev Oncol Hematol 34: 111–126

    Article  CAS  Google Scholar 

  8. Majumdar AS et al. (2001) The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters. Gene Ther 8: 568–578

    Article  CAS  Google Scholar 

  9. Takeda T (2003) Tumor-specific gene therapy for undifferentiated thyroid carcinoma utilizing the telomerase reverse transcriptase promoter. J Clin Endocrinol Metab 88: 3531–3538

    Article  CAS  Google Scholar 

  10. Plumb JA et al. (2001) Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954. Oncogene 20: 7797–7803

    Article  CAS  Google Scholar 

  11. Bilsland AE et al. (2003) Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Oncogene 22: 370–380

    Article  CAS  Google Scholar 

  12. Komata T et al. (2001) Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter. Cancer Res 61: 5796–5802

    CAS  PubMed  Google Scholar 

  13. Liu J et al. (2002) Cancer-specific killing by the CD suicide gene using the human telomerase reverse transcriptase promoter. Int J Oncol 21: 661–666

    CAS  PubMed  Google Scholar 

  14. Koga S et al. (2001) FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo. Anticancer Res 21: 1937–1943

    CAS  PubMed  Google Scholar 

  15. Koga S et al. (2000) A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter. Hum Gene Ther 11: 1397–1406

    Article  CAS  Google Scholar 

  16. Komata T et al. (2001) A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter. Int J Oncol 19: 1015–1020.

    CAS  PubMed  Google Scholar 

  17. Gu J et al. (2002) A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo. Oncogene 21: 4757–4764

    Article  CAS  Google Scholar 

  18. Lin T et al. (2002) Targeted expression of green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand fusion protein from human telomerase reverse transcriptase promoter elicits antitumor activity without toxic effects on primary human hepatocytes. Cancer Res 62: 3620–3625

    CAS  PubMed  Google Scholar 

  19. Jacob D et al. (2004) Suppressing orthotopic pancreatic tumor growth with a fiber-modified adenovector expressing the TRAIL gene from the human telomerase reverse transcriptase promoter. Clin Cancer Res 10: 3535–3541

    Article  CAS  Google Scholar 

  20. Gu J et al. (2002) hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity. Gene Ther 9: 30–37

    Article  CAS  Google Scholar 

  21. Huang TG et al. (2003) Telomerase-dependent oncolytic adenovirus for cancer treatment. Gene Ther 10: 1241–1247

    Article  CAS  Google Scholar 

  22. Kim E et al. (2003) Ad-mTERT-Delta19, a conditional replication-competent adenovirus driven by the human telomerase promoter, selectively replicates in and elicits cytopathic effect in a cancer cell-specific manner. Hum Gene Ther 14: 1415–1428

    Article  CAS  Google Scholar 

  23. Wirth T et al. (2003) A telomerase-dependent conditionally replicating adenovirus for selective treatment of cancer. Cancer Res 63: 3181–3188

    CAS  PubMed  Google Scholar 

  24. Kawashima T et al. (2004) Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res 10: 285–292

    Article  CAS  Google Scholar 

  25. Zou W et al. (2004) A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent. Oncogene 23: 457–464

    Article  CAS  Google Scholar 

  26. Lanson NA et al. (2003) Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis. Cancer Res 63: 7936–7941

    CAS  PubMed  Google Scholar 

  27. Irving J et al. (2004) Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity. Cancer Gene Ther 11: 174–185

    Article  CAS  Google Scholar 

  28. Wang J et al. (2003) Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation. FEBS Lett 546: 315–320

    Article  CAS  Google Scholar 

  29. Nettelbeck DM et al. (2000) Gene therapy: designer promoters for tumor targeting. Trends Genet 16: 174–181

    Article  CAS  Google Scholar 

  30. Galanis E et al. (2001) Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors. Crit Rev Oncol Hematol 38: 177–192

    Article  CAS  Google Scholar 

  31. Kyo S and Inoue M (2002) Complex regulatory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene 21: 688–697

    Article  CAS  Google Scholar 

  32. Soder AI et al. (1998) Tumour specific regulation of telomerase RNA gene expression visualized by in situ hybridization. Oncogene 16: 979–983

    Article  CAS  Google Scholar 

  33. Feng J et al. (1995) The RNA component of human telomerase. Science 269: 1236–1241

    Article  CAS  Google Scholar 

  34. Guilleret I et al. (2002) The human telomerase RNA gene (hTERC) is regulated during carcinogenesis but is not dependent on DNA methylation. Carcinogenesis 23: 2025–2030

    Article  CAS  Google Scholar 

  35. Muller M et al. (1998) Comparison of human telomerase RNA and telomerase activity in urine for diagnosis of bladder cancer. Clin Cancer Res 4: 1949–1954

    CAS  PubMed  Google Scholar 

  36. Takakura M et al. (1999) Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res 59: 551–557

    CAS  PubMed  Google Scholar 

  37. Cong YS et al. (1999) The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet 8: 137–142

    Article  CAS  Google Scholar 

  38. Wick M et al. (1999) Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT). Gene 232: 97–106

    Article  CAS  Google Scholar 

  39. Zhao JQ et al. (1998) Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene 16: 1345–1350

    Article  CAS  Google Scholar 

  40. Martin-Rivera L et al. (1998) Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc Natl Acad Sci USA 95: 10471–10476

    Article  CAS  Google Scholar 

  41. Greenberg RA et al. (1998) Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene 16: 1723–1730

    Article  CAS  Google Scholar 

  42. Zhao JQ et al. (2000) Activation of telomerase RNA gene promoter activity by NF-Y, Sp1, and the retinoblastoma protein and repression by Sp3. Neoplasia 2: 531–539

    Article  CAS  Google Scholar 

  43. Greenberg RA et al. (1999) Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18: 1219–1226

    Article  CAS  Google Scholar 

  44. Groot-Wassink T et al. (2004) Noninvasive imaging of the transcriptional activities of human telomerase promoter fragments in mice. Cancer Res 64: 4906–4911

    Article  CAS  Google Scholar 

  45. Vasey PA and Evans TRJ (2002) Principles of chemotherapy and drug development. In Treatment of Cancer, 103–129 (Eds Price P and Sikora K) London: Arnold Publishers

    Google Scholar 

  46. Gottesman MM (2003) Cancer gene therapy: an awkward adolescence. Cancer Gene Ther 10: 501–508

    Article  CAS  Google Scholar 

  47. Palmer DH et al. (2004) Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer. J Clin Oncol 22: 1546–1552

    Article  CAS  Google Scholar 

  48. Vasey PA et al. (2002) Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 20: 1562–1569

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in the author's laboratory is supported by Cancer Research UK, and Glasgow University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W Nicol Keith.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

BYSTANDER EFFECT

Tumor regression when a fraction of the tumor mass is genetically modified

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keith, W., Bilsland, A., Hardie, M. et al. Drug Insight: cancer cell immortality—telomerase as a target for novel cancer gene therapies. Nat Rev Clin Oncol 1, 88–96 (2004). https://doi.org/10.1038/ncponc0044

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc0044

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing