In perspective: An update on telomere targeting in cancer

Abstract

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.

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

“…Telomerase activity is not expressed in normal somatic cells, with the exception of few cell compartments (e.g., embryonic and multipotent stem cells, lineage progenitor cells) where it may become transiently activated and subsequently silenced upon differentiation [7]. Contrarily, telomerase activity is readily detectable in about 85-90% of human tumors, especially those of epithelial origin [5].…”

“…Contrarily, telomerase activity is readily detectable in about 85-90% of human tumors, especially those of epithelial origin [5]. Hence, the possibility to interfere with its expression and/or function for therapeutic purposes has been actively pursued [4][5][6][7].…”

Crossroads of telomere biology and anticancer drug discovery

“…6-Thio-dG has been effective against various cancers, including NRAS-driven melanoma, BRAF inhibitor/ immunotherapy-resistant melanoma, therapy-resistant lung cancer, and pediatric brain cancer in preclinical settings. 41 In 6-thio-dG-resistant cancer cells, SLC43A3, an equilibrative nucleobase transporter, is downregulated and is thus proposed as a biomarker for the drug sensitivity. 42 To date, the relationship between types of TERT gene abnormalities and the effects of telomere-directed therapeutics remain speculative.…”

Myocardial Cell Aging in the Elderly

“…Furthermore, the expression of telomerase and the maintenance of telomere function are related to tumorigenesis. Therefore, caution is necessary in the development of interventional treatments involving telomeres, such as telomere shortening inhibition and the maintenance of telomerase activity [14]. Antiaging therapies related to telomeres and DNA damage still need further study and discussion.…”