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Telomerase and cancer therapeutics

Key Points

  • Telomerase is an important drug target for cancer. It is expressed in most tumours from virtually all types of cancers and is required for long-term maintenance of telomeres, which in turn is crucial for the long-term survival of tumour cells.

  • Telomerase is a relatively specific cancer target as normal body cells express little or no telomerase for most of their lifespan and generally have longer telomeres than those in tumour cells.

  • Two major approaches to killing telomerase-positive tumour cells are in clinical trials. A direct telomerase inhibitor, GRN163L, is in trials in chronic lymphocytic leukaemia, multiple myeloma, solid tumours and non-small-cell lung cancer. Several therapeutic vaccines directed against the crucial telomerase protein TERT are in or have completed trials in leukaemia and renal, prostate, lung, skin, pancreatic and breast cancer.

  • Telomerase inhibitors can have fast-acting single-agent activity in certain cancers with short telomeres and rapid turnover, but this should not be the expectation in most patients.

  • Putative cancer stem cells are telomerase-positive and thus telomerase inhibitors, in combination with effective tumour de-bulking agents, might help meet a major unmet need: durability of response.

  • Telomerase vaccines offer the potential to stimulate the rapid killing of tumour cells by enhancing the activity of telomerase-specific cytotoxic (CD8+) and/or helper (CD4+) T cells. No significant toxicity to normal tissues has been seen in any of animal studies or clinical trials to date.

  • Potential challenges in the clinical development of telomerase-based cancer therapies include selection of the best patient population, good pharmacodynamic or biological markers to assess early activity, and optimal dose and schedule for combination therapies.

Abstract

Telomerase is an attractive cancer target as it appears to be required in essentially all tumours for immortalization of a subset of cells, including cancer stem cells. Moreover, differences in telomerase expression, telomere length and cell kinetics between normal and tumour tissues suggest that targeting telomerase would be relatively safe. Clinical trials are ongoing with a potent and specific telomerase inhibitor, GRN163L, and with several versions of telomerase therapeutic vaccines. The prospect of adding telomerase-based therapies to the growing list of new anticancer products is promising, but what are the advantages and limitations of different approaches, and which patients are the most likely to respond?

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Figure 1: Telomerase is an RNA-dependent reverse transcriptase in which the templating RNA (telomerase RNA component (hTR)) is integral to the enzyme.
Figure 2: Five telomerase-based approaches to killing tumour cells are illustrated in order of their anticipated pharmaceutical potential.

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Competing interests

Calvin B. Harley is a shareholder, employee and officer with Geron Corporation.

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DATABASES

National Cancer Institute

bladder cancer

brain cancer

breast cancer

cervical cancer

liver cancer

lung cancer

lymphoma

melanoma

multiple myeloma

ovarian cancer

pancreatic cancer

prostate cancer

renal cell cancer

National Cancer Institute Drug Dictionary

 carboplatin

GRN163L

paclitaxel

FURTHER INFORMATION

Geron Corporation

Shay/Wright Laboratory

University of Utah Learn Genetics

Glossary

Replicative senescence

Cell-cycle arrest after a characteristic number of cell divisions (the 'Hayflick limit'), typically triggered by a DNA damage checkpoint associated with one or more dysfunctional telomeres.

Crisis

A cellular state characterized by massive genomic instability and a high probability of cell death due to critically short telomeres.

Cancer stem cell

An immortal cancer cell with self-renewing capacity and the ability to create or sustain a tumour cell population. For some tumour types, relatively non-stringent assays have been used to identify putative cancer stem cells.

Therapeutic window

The range of doses or window of time in which a drug is therapeutically active without being unacceptably toxic.

Suicide genes

Genes that, when actively expressed, lead to death of the cells. Expression of suicide genes is controlled by promoters (genetic regulators) that are preferentially activated in tumour cells (for example, telomerase promoters). Examples are genes that encode proteins that control replication of oncolytic viruses or enzymes that convert a prodrug into a toxic substance.

Ribonucleoprotein

An association of protein and RNA. Telomerase is an example of a ribonucleoprotein with a specific enzymatic activity.

G-quadruplex

A four-stranded nucleic acid structure stabilized by non-Watson–Crick base-pairing within stacks of four planar-orientated guanosine nucleotides. G-quadruplex structures can form within or between G-rich strands of telomeric DNA.

Major histocompatibility complex (MHC) class I and class II

The MHC genes encode proteins that process and bind antigens (peptide fragments from self or non-self proteins). The antigen-binding proteins reside on the cell surface and present antigens to the T-cell receptor on T cells. Class I MHC-encoded proteins are expressed on all nucleated cells (including tumour cells and antigen-presenting cells) and display their antigen to cytotoxic T cells by binding CD8. Class II MHC-encoded proteins are expressed on specialized antigen-presenting cells, which present their antigen to T-helper cells by binding CD4.

Human leukocyte antigen

(HLA). HLA genes are part of the major histocompatibility complex and encode the proteins that bind and present antigens to T cells.

Antigen-presenting cell

Cells such as dendritic cells, macrophages and B cells that inherently express both major histocompatibility complex class I and class II genes and present antigen to T cells.

Prostate-specific antigen velocity

The rate of increase in levels of prostate-specific antigen circulating in plasma.

Granulocyte–macrophage colony-stimulating factor

A growth factor that stimulates production and migration of granulocytes and monocytes.

Phenotypic lag

The delay between the initiation of telomere loss by telomerase inhibition and the arrest of cell proliferation owing to a dysfunctional telomere.

Alternative lengthening of telomeres

(ALT). A recombination pathway for telomere maintenance observed in some telomerase-negative cells (in vitro and in vivo).

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Harley, C. Telomerase and cancer therapeutics. Nat Rev Cancer 8, 167–179 (2008). https://doi.org/10.1038/nrc2275

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