Oligonucleotides Targeting Telomeres and Telomerase in Cancer

Abstract

Telomeres and telomerase have become attractive targets for the development of anticancer therapeutics due to their involvement in cancer cell immortality. Currently, several therapeutics have been developed that directly target telomerase and telomeres, such as telomerase inhibitors and G-quadruplex stabilizing ligands. Telomere-specific oligonucleotides that reduce telomerase activity and disrupt telomere architecture are also in development as novel anticancer therapeutics. Specifically, GRN163L and T-oligos have demonstrated promising anticancer activity in multiple cancers types via induction of potent DNA damage responses. Currently, several miRNAs have been implicated in the regulation of telomerase activity and may prove to be valuable targets in the development of novel therapies by reducing expression of telomerase subunits. Targeting miRNAs that are known to increase expression of telomerase subunits may be another strategy to reduce carcinogenesis. This review aims to provide a comprehensive understanding of current oligonucleotide-based anticancer therapies that target telomeres and telomerase. These studies may help design novel therapeutic approaches to overcome the challenges of oligonucleotide therapy in a clinical setting.

Telomeres and Telomere Length: A General Overview

“…Telomeres are also targeted using guanine-rich oligonucleotide (GRO) homologous to the 3 single-stranded overhang, known as T-oligos, a specific 11-base oligonucleotide sequence, (5 GTTAGGGTTAG), which accumulates in the nucleus and induces DDR with minimal or no functional effect on normal cells [250,253]. Treatment with T-oligos in vitro has been shown to be effective in reducing viability and tumor growth in several cancers, including melanoma, prostate, ovarian, lung, breast, and colorectal cancer [250,[254][255][256][257][258]. T-oligos are hypothesized to interfere with normal telomeric structure and form G-quadruplexes, inducing genomic stress in addition to aberrant upregulation of DDR pathways, and TRF2 and POT1 have shown to be upregulated after T-oligo treatment [250,254,259].…”

Drug Targeting of Genomic Instability in Multiple Myeloma

“…The BFB cycle was reported to be associated with CIN development and peri-centromeric instability in MM (Sawyer et al, 2009). The most promising drug to specifically target telomerase is GRN163L, a synthetic lipid-conjugated 13-mer N3→P5 thio-phosphoramidate deoxyribo-oligonucleotide that blocks the template zone of telomerase and has potential antineoplastic activity (Schrank et al, 2018) (Figure 1). A study using myeloma cell lines found that prominent inhibition of telomerase activity with GRN1613L led to a reduction in viability to < 5% of baseline levels over a period of three to 5 weeks (Shammas et al, 2008) (Table 1).…”

Therapeutic strategies for targeting telomerase in cancer

“…In addition, there are few studies on the mechanisms of T‐oligo in ALT cancer cells. In 2018, T‐oligo was extensively reviewed by Schrank et al, and therefore, we will not repeat it in this review …”