Telomerase as a therapeutic Bullseye: advances in cancer treatment and clinical trials : A comprehensive review of small molecule inhibitors, antisense oligonucleotides, and immunotherapeutic strategies targeting the telomerase catalytic subunit (hTERT).

内容摘要

Telomeres play a crucial role in maintaining genomic stability in healthy cells. However, they gradually shorten during the cell cycle, leading to chromosomal instability. Telomere length and telomerase activity are vital factors that counteract cellular degradation in cancer development and tumor persistence. Telomerase, which is activated in most cancer cells due to telomerase catalytic subunit (hTERT) overexpression, serves as a universal biomarker that is essential for cancer cell growth and survival. The upregulation of hTERT, often associated with G > A mutations in its promoter region, is frequently implicated in cancer progression. Consequently, anti-telomerase therapy has been proposed as a potentially more efficacious alternative to conventional treatment. Small-molecule inhibitors have garnered significant attention owing to their selectivity or ability to modulate multiple proteins. However, challenges, such as low response rates, brief response durations, toxicity, and resistance persist. Several strategies have been proposed to target telomerase activity and the telomere structure. These include the utilization of G-quadruplex-stabilizing compounds and telomere-specific oligonucleotide inhibitors of telomerase such as GRN163L and T-oligos. Another therapeutic approach involves the use of biological antisense oligonucleotides that specifically inhibit hTERT and human telomerase RNA component genes, potentially reducing telomerase activity and generating robust DNA signals in cancer cells. Immunotherapy targeting hTERT represents a recent advancement in cancer treatments. This approach leverages the immune system to target cancer cells with high hTERT expression, thereby offering a potentially more reliable treatment strategy. This review provides an overview of current research on telomerase-targeting small-molecule inhibitors, antisense oligonucleotides, and immunotherapy, discussing their mechanisms, clinical applications, and prospects in cancer treatment.