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Telomerase therapeutics for cancer: challenges and new directions

Key Points

  • Telomeres are the linear ends of chromosomes and are important in completing DNA replication. Telomeres and telomere-associated proteins cap the chromosome ends, preventing recombination, end-to-end fusions and degradation. Telomeres progressively shorten throughout life and most pre-cancerous lesions have very short telomeres.

  • Immortalization is required for most advanced human malignancies to continue to divide. The cellular reverse transcriptase telomerase is upregulated in almost all cancers and permits the indefinite growth of human cancer cells.

  • Approaches that specifically interfere with telomerase represent a novel targeted cancer therapy forcing cells back into a senescent or apoptotic pathway.

  • Clinical trials targeting telomerase include vaccines that recognize telomerase epitopes inappropriately expressed on tumour cells and small-molecule inhibitors such as a 13-mer oligonucleotide called GRN163L

  • Other approaches in preclinical studies include a telomerase-specific oncolytic virus that exclusively replicates in and lyses cells that actively express telomerase.

  • Most cancers are heterogeneous and contain cancer stem cells as well as more differentiated cancer cells. It is now known that telomerase is expressed in at least some types of cancer stem cells and that they contain short telomeres. Therefore, telomerase inhibitors could also target cancer stem cells.

Abstract

It has been approximately a decade since telomerase was described as an almost universal marker for human cancer. Most human tumours not only express telomerase but also have very short telomeres, whereas telomerase activity is either reduced or absent in normal tissues, making the inhibition of telomerase an attractive target for cancer therapeutics. Here we review the current status of telomerase therapeutics and discuss future opportunities and challenges for telomerase research, including a possible relationship with cancer stem cells that could be a source of chemo-/radioresistance development in many advanced cancers.

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Figure 1: Telomerase components.
Figure 2: Comparing telomerase inhibition in normal versus cancer cells.
Figure 3: Predicted outcomes of telomerase therapy.

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Acknowledgements

The authors acknowledge support from the Southland Foundation Distinguished Chair in Geriatrics Research, the Ellison Medical Foundation, and NSCOR and National Cancer Institute grants. We also acknowledge A. Diehl for providing drafts of the figures used in this review.

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Correspondence to Jerry W. Shay.

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Glossary

Replicative senescence

The process by which most normal human cells 'count' the number of times they have divided, eventually undergoing an irreversible growth arrest due to telomere shortening on a few chromosome ends.

Mitotic catastrophe

A response to abnormal mitotic DNA damage, leading to cell death. Normal cells avoid mitotic catastrophe by activating different cell-cycle checkpoint genes, which allows cells to repair the damage before mitosis; this mechanism is absent in checkpoint-deficient cells with critically shortened telomeres.

Telomerase reverse transcriptase

(hTERT). The catalytic subunit of telomerase (an RNA-dependent DNA polymerase) that synthesizes telomeric repeats onto the end of telomeres using the integral RNA (hTR) component as a template.

Telomerase RNA

(hTR/hTERC). The integral RNA that provides an 11-bp template complementary to the telomeric repeats to be added to the chromosome.

Crisis

A balance between cell growth and cell death. When cells bypass replicative senescence, telomeres continue to shorten, eventually leading to mitotic catastrophe. These cells die or, rarely, reactivate telomerase, leading to an immortalized cell line.

Cancer stem cells

A small subset of tumour cells that can recreate and sustain (re-initiate, re-populate) the tumour in a functional transplant assay. It is believed that cancer stem cells have multilineage potential and might be responsible for the failure of current therapies.

Prostate-specific antigen

A serine protease in the kallikrein gene family that is secreted into seminal fluid by prostatic epithelial cells and found in the serum. As it is almost exclusively a product of prostate cells, measurement in blood has proved to be exceptionally useful as a tumour marker for diagnosis of prostate cancer and monitoring the effectiveness of treatment.

Xenograft

Transplantation of tissue or cells from one species to another. In cancer research, most xenografts are human cancer cell lines or human tumours that have been transplanted to immune-deficient rodents.

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Shay, J., Wright, W. Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov 5, 577–584 (2006). https://doi.org/10.1038/nrd2081

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