In perspective: An update on telomere targeting in cancer.

Journal Article (Journal Article;Review)

Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.

Full Text

Duke Authors

Cited Authors

  • Sugarman, ET; Zhang, G; Shay, JW

Published Date

  • September 2019

Published In

Volume / Issue

  • 58 / 9

Start / End Page

  • 1581 - 1588

PubMed ID

  • 31062416

Pubmed Central ID

  • PMC6692182

Electronic International Standard Serial Number (EISSN)

  • 1098-2744

Digital Object Identifier (DOI)

  • 10.1002/mc.23035

Language

  • eng

Conference Location

  • United States