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New prospects for targeting telomerase beyond the telomere

Key Points

  • Telomerase is a ribonucleoprotein complex responsible for maintaining chromosome-end structures called telomeres. Telomerase activity enables unlimited cell proliferation (immortality) in diverse human cancers.

  • Despite the cloning of the catalytic component of telomerase approximately 20 years ago and the central role of telomerase in diverse cancers, only one small-molecule telomerase inhibitor, imetelstat, has been tested in clinical trials.

  • Components of the telomerase complex have extra-telomeric activities that may contribute to cancer cell survival, proliferation and malignancy.

  • Recent advances in drug discovery technology may be leveraged in the identification and development of novel small-molecule inhibitors that simultaneously disrupt telomere maintenance and the non-canonical activities of telomerase components.

  • This Review outlines strategies for harnessing state-of-the-art drug discovery techniques to find novel cancer therapeutics that exploit multifaceted biological functions of core components of telomerase.

Abstract

Telomerase activity is responsible for the maintenance of chromosome end structures (telomeres) and cancer cell immortality in most human malignancies, making telomerase an attractive therapeutic target. The rationale for targeting components of the telomerase holoenzyme has been strengthened by accumulating evidence indicating that these molecules have extra-telomeric functions in tumour cell survival and proliferation. This Review discusses current knowledge of the biogenesis, structure and multiple functions of telomerase-associated molecules intertwined with recent advances in drug discovery approaches. We also describe the fertile ground available for the pursuit of next-generation small-molecule inhibitors of telomerase.

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Figure 1: Telomerase biogenesis and targeting strategies.

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Acknowledgements

The Children's Cancer Institute Australia is affiliated with University of New South Wales, Australia, and the Sydney Children's Hospitals Network. The authors acknowledge financial support from the Cancer Council New South Wales (RG 15-16), the Australian Cancer Research Foundation, the Cancer Institute New South Wales (15/RIG/1-01), Therapeutic Innovation Australia (NCRIS 2015) and Cancer Therapeutics CRC.

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Correspondence to Karen L. MacKenzie.

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Glossary

Alternative lengthening of telomeres

A recombination-based mechanism of telomere lengthening that operates in cancer cells in the absence of telomerase.

High-content imaging

Automated imaging of fluorescent stains or tags used to quantify changes in specific cellular processes, phenotypes or subcellular components.

G-quadruplex

A nucleic acid secondary structure that forms in guanine-rich regions involving the stacking of square planar structures each formed by four guanines.

Essential thrombocythaemia

A rare blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow.

Myelofibrosis

A rare clonal bone marrow disorder in which haematopoiesis is overtaken by the production of fibrous tissue.

Thrombocytopenia

A disorder featuring abnormally low platelet counts.

Megakaryocyte

A bone marrow cell that produces small cell bodies called platelets that are involved in blood clotting.

Nucleotide excision repair

A multistep DNA repair mechanism that removes and repairs DNA damage caused by radiation and chemicals.

Terminal transferase

A template-independent polymerase that adds deoxynucleotides to the 3′ hydroxyl terminus of DNA.

AlphaScreen technology

(amplified luminescent proximity homogeneous assay screen). A homogeneous bead-based proximity assay used to measure the interaction between two biological molecules.

Small nucleolar RNAs

(snoRNAs). A class of small RNA molecules localized in nucleoli that guide chemical modifications of other RNAs, such as rRNAs and tRNAs.

Small Cajol body-specific RNAs

(scaRNAs). Small RNAs that specifically localize to Cajal bodies and function to guide the modification (methylation and pseudouridinylation) of spliceosomal RNAs.

Cajal bodies

Nuclear organelles adjacent to nucleoli in proliferating cells that are involved in the biogenesis of small nuclear ribonucleoproteins.

Solution-based two-dimensional combinatorial screening

An array-based method for identifying interactions between specific RNA motifs and small molecules.

Dyskeratosis congenita

A rare inherited disorder caused by mutation in the DKC1 gene (which encodes dyskerin) and characterized by multiple organ failure.

Structure-based design

A form of rational drug design that relies on the three-dimensional structure of a specific biomolecular target.

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Arndt, G., MacKenzie, K. New prospects for targeting telomerase beyond the telomere. Nat Rev Cancer 16, 508–524 (2016). https://doi.org/10.1038/nrc.2016.55

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