The role of telomere and telomerase in cancer and novel therapeutic target: narrative review

Telomeres are dynamic complexes at the ends of chromosomes that are made up of protective proteins and tandem repeating DNA sequences. In the large majority of cancer cells, telomere length is maintained by telomerase, an enzyme that elongates telomeres. Telomerase activation is seen in the majority of cancer, which permits uncontrol cell proliferation. About 90% of human malignancies show telomere dysfunction and telomerase reactivation; as a result, telomerase activation plays a special role as a practically universal stage on the way to malignancy. This review understands the structural and functional of telomere and telomerase, mechanisms of telomerase activation in oncogenesis, biomarkers and therapeutic targets. Therapeutic strategies targeting telomerase, including antisense oligonucleotides, G-quadruplex stabilizers, immunotherapy, small-molecule inhibitors, gene therapy, Telomerase-Responsive Drug Release System, have shown promise in preclinical and clinical settings. Advances in telomere biology not only illuminate the complex interplay between telomeres, telomerase, and cancer progression but also open avenues for innovative, targeted cancer therapies.

Introduction

Telomeres are dynamic complexes at the ends of chromosomes that are made up of protective proteins and tandem repeating DNA sequences (1). Telomeres primary job is to prevent chromosome ends from being identified as double-strand DNA damage by compaction of telomere chromatin, shelterin recruitment, and structural modifications (2). When a critical telomere length is reached, shelterin will lose its binding site and telomeric DNA cannot form a protective secondary structure (3). Oncogenic cells avoid senescence and divide infinitely until numerous severely shortened telomeres trigger a crisis (4). But occasionally, rare cells manage to avoid crises and continue to proliferate by maintaining stable, albeit typically reduced, telomere lengths. Eventually, these cells develop into malignant phenotypes. The proliferative immortality of cancer cells is attained through the activation or upregulation of the normally silent human telomerase reverse transcriptase (TERT) gene (hTERT), which encodes telomerase. Rarely, telomere attrition is reversed by an additional DNA recombination mechanism known as alternative lengthening of telomeres (ALT), which avoids senescence (5). Approximately 90% of human malignancies have considerable expression of hTERT, despite the fact that it is normally repressed in almost all somatic cells. Although the exact mechanisms behind hTERT activation are still unknown, they primarily involve mutations in the hTERT promoter, modifications in hTERT pre-mRNA alternative splicing, hTERT amplification, epigenetic modifications, and/or disruption of the telomere position effect (TPE) machinery. Two cancer-specific hTERT promoter mutations, primarily C T transitions, have been linked in recent findings to the activation of telomerase in cancer cells (6). Currently, many anti-telomerase therapeutics are being evaluated in clinical trials against a variety of cancer types. The following sections will cover recent developments in the area of Structure and Function of Telomere- Telomerase, Carcinogenic mechanisms dependent on telomeres and telomerase and for the development of cancer therapies.

Structure and function of telomere-telomerase

The protective end caps of chromosomes known as telomeres are crucial to the maintenance of our genome. Telomeres are made up of millions of repeating DNA base pairs that do not express any known proteins (7). The sequence 5′-(TTAGGG) n-3′ represents the final telomeric repeat in humans and a number of other species. The distal portion of the telomere terminates in a single-stranded G-rich segment with a shorter 5′-chain than a double strand of DNA (8). Telomeres are essential for many biological functions because they shield chromosomes against chromosomal instability and end-to-end fusions. The protective protein complex known as Shelterin binds the repeated TTAGGG sequences that make up telomeric DNA. This complex forms the telomere structure, safeguarding chromosomal ends, together with proteins involved in chromatin remodeling (7). The chromosomal ends creation of DNA loops (T-loops) and the transcription of telomeres to produce G-rich RNA. The G-rich strands 3′ end projects as the G-overhang, a single stranded overhang in the T-loop structure. This G-strand overhang invades the 5′ double-stranded telomeric duplex, looping back to generate a T-loop and the so-called D-loop. This structure ensures that loose DNA ends are housed internally within the nucleoprotein structure (9). The formation of such looped structures is an important mechanism that protects telomeres from premature degradation. Telomeres are capable of being actively transcribed while being heterochromatic, which leads to the synthesis of lengthy non-coding RNAs known as TERRAs (telomeric repeat-containing RNA). TERRA molecules are essential for controlling telomerase activity and forming heterochromatin at chromosomal ends (10).

Shelterin subunits (Figure 1), TRF1 and TRF2, which directly recognize and bind duplex TTAGGG repeats, and POT1, which recognizes and binds single-stranded TTAGGG overhangs, make form the protein complex known as the shelterin complex, which is linked to telomeres (11). Three other shelterin proteins, TIN2, TPP1, and RAP1, link these three proteins together to produce a complex that allows DDR surveillance equipment to discriminate between genomic DNA damage sites and telomere DNA. Telomere stability is maintained by the crucial and unique functions carried out by the shelterin complex (12). For T-loop formation and ATM-mediated DDR suppression and repression from non-homologous end joining to continue, TRF2 is necessary. POT1 binds the single-stranded 3′ overhang and represses ATR-mediated DDR by blocking the recruitment of replication protein A (RPA), whereas TRF1 plays a crucial role in regulating telomeric DNA replication (13). Since TIN2 stabilizes TRF1 and TRF2 interactions with telomeric DNA and connects the TPP1/POT1 heterodimer to TRF1 and TRF2, it is critical to the overall stability of the shelterin complex. TRF2 and RAP1 interact to enhance TRF2 ability to bind to telomeric DNA selectively (14).

Figure 1

Figure 1. Telomere structure, shelterin complex and telomerase.

Long arrays of tandem TTAGGG repeats, which can range in length from 15 kb to more, make up telomeres. Two components of the shelterin complex, TRF1 and TRF2, bind to the TTAGGG/CCCTAA duplexes. In addition to bridging TRF1 and TRF2, the subunit TIN2 (TRF1-interacting nuclear factor 2) interacts with a third partner, the subunit. TPP1 interacts with POT1 (protection of telomere 1), which strengthens the cohesiveness of the nucleoprotein complex by binding the 3′ single-stranded overhang with its two OB fold domains. Lastly, the final member of Shelterin, RAP1, only interacts to TRF2. A telomerase reverse transcriptase (hTERT), an RNA component (hTERC or hTR), and a number of other protein factors, including dyskerin (DKC1), NHP2, NOP10, and GAR1, which are also components of the H/ACA ribonucleoprotein complex, make up the holoenzyme of telomerase, a retro-transcriptase.

Telomerase is a reverse transcriptase enzyme capable of extending severely short (“uncapped”) telomeres to stabilize their length. It is highly active during the early stages of human development but becomes inactivated in most adult cells. Exceptions include immune cells, germ line cells, and embryonic stem cells, where telomerase activity is maintained. Notably, telomerase is reactivated in the majority of cancers, contributing to their uncontrolled growth (15). A catalytic subunit with reverse transcriptase activity called TERT-telomerase reverse transcriptase, an RNA template called TERT-telomerase RNA component that has a sequence complementary to the telomere’s sequence, and accessory proteins like discerin, NHP2 ribonucleoprotein, NOP10 ribonucleoprotein, and GAR1 (localization factor) make up the enzyme telomerase (16). The protein complex and TERC are bound by the TERT subunit. Telomerase interacts with the telomere-localizing protein TPP1 to attract it to single-stranded telomeric DNA. The ATPases pontin and reptin, the chaperones HSP90 and p23, a WD-repeat-containing protein 79 known as TCAB1, and other components are also involved in this process. The telomerase-telomere complex is stabilized by the TERC-blinding protein, SRSF11 (17). The transcription factors c-MYC and SP1 must bind to the E-box (5′-CACGTG-3′) and five GC boxes (5′-GGGCGG-3′) in order to induce the production of TERT mRNA (18).

The transcriptional reactivation of TERT in cancer cells is mediated by many signaling pathways, primarily c-MYC, NF-κB, and B-Catenin. Furthermore, through phosphorylation, the PI3K/AKT kinase pathway increases TERT activity at the posttranslational level. When c-MYC binds to the E-box (5′-CACGTG-3′) in the TERT promoter region, TERT is activated. The activation of TERT transcriptional activity, stabilization of c-MYC levels on chromatin, c-MYC ubiquitination, and proteosomal degradation lead to an increase in vascular cell survival and stimulation of c-MYC-dependent oncogenesis potential (19). Through NF-κB binding sites in the TERT promoter that are specific for p50 and p65, NF-κB regulates the transcription of TERT.In addition to causing TERT transcription activities, this pathway also modifies TERT nuclear translocation, recruits IL6 and TNF alpha, represses ROS-dependent activation, and increases MMP. These actions lead to the suppression of inflammation, ROS-dependent activation, and the advancement of cancer. TERT regulation also involves the Wnt/B-Catenin pathway (20).

Telomerase: the key telomere length maintenance mechanism

Telomerase maintains telomere length (TL) through a series of molecular events. These include the transport of (human telomerase reverse transcriptase) hTERT protein into the nucleus, the assembly of (human telomerase RNA) hTR and hTERT with accessory components within the nucleus, and the recruitment of telomerase to telomeres during DNA replication. The hTERT is a catalytic subunit, while hTR serves as a template for telomere elongation (21). Other proteins, dyskerin, NHP2, NOP10, and GAR1 (localization factor), that are linked to the H/ACA family of short nucleolar RNAs, are also part of the telomerase holoenzyme and are required for the pseudo uridylation that occurs during the post-transcriptional modification of RNAs. The CAB-box sequence in the hTR is bound by WD-repeat-containing protein 79, or TCAB1, that then directs the telomerase holoenzyme to the Cajal bodies attached to the nucleolus (22). These molecular players are chaperones HSP90 and p23, as well as the ATPases pontin and Reptin, known to bind to telomerase’s major two subunits. This allows for the proper assembly and stabilization of telomerase into its holoenzyme form (23); the most biologically plausible human telomerase model would involve a process that could yield the scaffold assembly platform for dyskerin, the nascent forms of hTR transcripts, together with pontin and Reptin. Subsequently, the telomerase RNP particle then interacts with NHP2 ribonucleoprotein, NOP10 ribonucleoprotein, a nuclear assembly factor ribonucleoprotein (NAF1), and the dyskerin H/ACA motif-binding complex. Subsequently, NAF1 is removed by hTR and GAR1 added, forming a physiologically stable hTR-H/ACA-RNP complex. The catalytically active telomerase RNP is produced when hTERT binds to two structurally distinct hTR domains (CR4/CR5) after the hTR 3′-hairpin CAB-box sequence recruits TCAB1 (24).

Telomerase can only be recruited to telomeres after the replication fork remodels the protected DNA 3′ ends during the S phase of the cell cycle (Figure 2). This process is dependent on protein-protein interactions involving the DAT (dissociates the activities of telomerase) domain of hTERT. These interactions distinguish its activity from an in vitro setting and allow it to interact with shelterin complex components, specifically TPP1 and POT1, which are essential for telomerase recruitment. This part of TPP1 is an amino acid patch known as the Tel patch located in the N-terminal oligonucleotide/oligosaccharide-binding (OB)-fold domain that directly interacts with the telomerase DAT domain (25). It also contains a C-terminal domain that binds to TIN2 and a central domain that directly interacts with POT1. Thus, the interaction between the DAT domain of hTERT and shelterin components ensures proper telomerase placement at the 3′ end of DNA for synthesis and processivity of telomeric repeats. SRSF11 is a new TERC-binding protein that is involved in the process of loading telomerase onto the telomeres. This therefore allows for stable interaction between the enzyme and the telomere overhang, such that the DNA 3′ end is correctly positioned near the active site of the enzyme for nucleotide addition. It thus plays a critical role in the maintenance of telomere integrity, and there may be serious implications for cell aging and diseases such as cancer resulting from disruptions in this process (26).

Figure 2

Figure 2. The main mechanism for maintaining telomere length.

In eukaryotic organisms, the cellular ribonucleoprotein enzyme complex known as telomerase is responsible for catalyzing the extension of telomeric DNA. A number of processes are involved in telomerase action, such as the telomerase complex’s construction, intracellular trafficking, and recruitment to telomeres. Human telomerase is made up of the auxiliary proteins dyskerin, NOP10, NHP2, and GAR1, as well as hTR (hTERC—a template functional RNA) and hTERT (the catalytic protein component with reverse transcriptase activity). In the cytoplasm, the hTERT protein binds to p23 and HSP90 before entering the nucleus. NHP2, GAR1, NOP10, and dyskerin form a complex with nascent hTR transcripts. This complex is bound to the hTERT +p23 + HSP90 complex via Reptin and Pontin. Then, TCAB1 binds to this assembling complex and directs it to the nucleus’ Cajal bodies. Through interactions between the DAT domain of hTERT and the shelterin complex components TPP1 and POT1, telomerase is recruited to telomeres during the S phase of the cell cycle. For DNA synthesis, SRSF11 maintains the telomerase enzyme complex’s attachment to the telomere overhang.

Telomerase used as cancer biomarker

Telomerase activity is highly upregulated in most of cancers that have been surveyed across in the vast majority of malignancies, including breast, colon (27, 28), melanoma (29), oral (30), ovarian (31), pancreas (32), prostate, and soft tissue cancer (33). Because of phenotypic difference between malignant and normal/benign tissues, telomerase used as a universal cancer biomarker for prognosis and diagnosis of cancer (34). The telomeric repeat amplification protocol (TRAP), a technique for assessing telomerase activity. This assay consists of two steps: an amplification reaction where any TS oligo extended by telomerase in the lysate is PCR amplified for detection, and an extension reaction where a “telomerase substrate” (TS) oligonucleotide mimicking a 3’ telomere end is combined with cell lysate containing telomerase (35). As little as 1–10 telomerase positive cells or 0.01% positive cells in a mixed population can be found with this extremely sensitive assay. Telomerase activity has been established using TRAP in the great majority of cancer types, but not in certain normal somatic tissues. However, TRAP activity was found in germ-line tissues, and weak activity was reported in specific stem cell populations and peripheral blood leukocytes (36).

TERT mRNA expression level has been investigated as a biomarker in addition to telomerase enzymatic activity since it has been shown to be the rate-limiting factor of telomerase activity in a number of cancers, including breast, non-small cell lung, and urothelial cancer (37). The expression of TERT mRNA is directly linked to the activation of telomerase, which is essential for tumor cell proliferation and immortality. The presence of plasma TERT mRNA was detected in patients with prostate cancer, with sensitivity at 85%, specificity at 90%, positive predictive value at 83%, and negative predictive value at 92%, making it a reliable diagnostic and prognostic tool (38). TERC, the telomerase RNA, has been thought to be an unsuitable cancer marker because, unlike TERT mRNA, it is often expressed widely and occasionally even in the absence of telomerase activity. Nonetheless, oesophageal cancer, gastric carcinomas, and astrocytomas all had noticeably higher TERC RNA levels (39). Although TERC expression is not tumour-specific its highly expressed level may be indicative of the presence of tumor in some cancer types. It is not detectable in benign tissue but is reported to be in 17/18 cases by real-time qPCR in all breast cancer tumors (40). qPCR, being a high sensitivity technique for amplifying the TERC RNA copy, is more sensitive and was indeed detectable with small amounts of tumor tissue. Recently, excreted urine from bladder cancer patients was tested for telomerase activity, TERT mRNA, and TERC telomerase RNA with a range of sensitivities and specificities (41). The utilization of urine as a non-invasive sample has the potential to allow for early detection of bladder cancer. Among these three techniques compared in urine from 200 bladder patients, the sensitivity of TERT mRNA, TERC, and telomerase activity for detecting bladder cancer were 96%, 92%, and 75%, respectively (42).

Telomerase as a therapeutic target in cancer treatment: exploring inhibition strategies

Developing effective treatments to combat cancer, telomerase is supposed to be a key target (43). Maintaining telomere lengths that are comparably long to those of cancer cells. These traits offer a benefit that guarantees a low chance of telomere shortening in healthy cells. Anti-telomerase medications primarily target cancer cells to cause apoptosis and cell death, with little to no effect on normal cells because somatic cells express very little or no telomerase (44). The majority of malignancies (85%–90%) exhibit telomerase activity. As a result, telomerase suppression presents an appealing target for cancer therapy. Numerous strategies, including antisense oligonucleotides, G-quadruplex stabilizers, immunotherapy, small-molecule inhibitors, gene therapy, Telomerase-Responsive Drug Release System have been developed in the hunt for telomerase inhibitors (45).

Oligonucleotides

The use of antisense oligonucleotides to prevent the translation of mRNA with a sequence complementary to sense RNA was the first description of the antisense oligonucleotide technique for targeting telomerase (69). Targeting the catalytic component of telomerase (hTERT), oligonucleotides are made up of short sequences of single-stranded DNA (SS-DNA) that bind to the RNA template in a complementary manner to limit telomerase activity. GRN163L is currently the most effective oligonucleotide. The treatment of human bladder cancer cells in vitro with oligonucleotides targeted to hTERT inhibits the cells’ ability to proliferate. Small interfering RNA (siRNA) operates through a mechanism involving small double-stranded RNA molecules that form an RNA-induced silencing complex (RISC). This complex binds to target mRNA and cleaves it, effectively silencing gene expression (46). The technique very well for short-term hTERT knockdown because the cells break down the dsRNA. Using plasmid constructs that exogenously express short hairpin RNA sequences to the hTERT transcript, RNA interference (RNAi) of hTERT has also been effective. This method permits long-term and permanent gene knockdown and acts as an alternative to gene therapy via viral vectors (47). Long-term hTERT knockdown can also be achieved by using retroviral vectors that express short hairpin RNA specific to a section of the hTERT transcript. Telomerase activity is competitively inhibited by Imetelstat. A 13-mer N3′–P5′ thiophosphoramide oligonucleotide is included in it, and a 5′-thio-phosphate group covalently bonds it to a palmitoyl moiety. The thiophosphonate backbone of Imetelstat possesses a variety of physicochemical characteristics, including excellent water solubility, metabolic stability, resistance to nuclease activity, and stability in the formation of RNA duplexes (48, 49). The sequence 5′-palmitate- TAGGGTTAGACAA-NH2- 3′ of Imetelstat binds to a complementary 13-nucleotide region of h TR, which exhibits great specificity and affinity to the active site of telomerase enzyme (12, 50).

Anti-telomerase immunotherapy

The main idea behind the hTERT-specific T cell therapy for anticancer immune cancers is to target telomerase positive malignancies. In actuality, the use of proteasomes to break down telomerase results in the production of telomerase protein fragments that are produced as antigens on the surface of tumor cells by the human leukocyte antigen (HLA) class-1 pathway (51). Thus, cytotoxic T lymphocytes can target antigenic telomerase epitopes to eliminate tumor cells. Telomerase-specific epitopes can activate antigen-presenting cells to assault tumor cells or trigger CD4+ or CD8+ cytotoxic T-lymphocyte responses. By sensitizing the immune system to the tumor cell’s presentation of hTERT peptides, this therapy produces increased anticancer effects by activating and generating CD8+ cells that are specific to h TERT (12). It’s interesting to note that cancer patients can stimulate anti-telomerase immune responses by administering three key vaccines: GV1001L, Vx001, and GRNVACI. It’s interesting to note that in both mice and humans, immunization with autologous dendritic cells transfected with hTERT mRNA also produces CD4+ and CD8+ T responses (52).

TERT-targeted peptide vaccines

Out of all the TERT vaccinations, GV1001 is the most advanced. It triggers certain T cell reactions in melanoma, NSCLC, and pancreatic cancer. Strong CD4+ and CD8+ T cell responses as well as the activation of cytotoxic T lymphocytes (CTL) are produced by this MHC class II restricted peptide vaccination (53). Prostate and kidney cancer patients have tested for GX301, a vaccine made up of four peptides generated from TERT that is more effective than single-peptide vaccines. These studies’ findings suggest that multi-peptide vaccinations are more successful than single-peptide vaccines because they boost the immune response in a greater number of responders (54). There has been evidence of immune responses to the UV1 or Vx-001 vaccines in NSCLC and prostate cancer, respectively. The first of them decreased prostate-specific antigen (PSA) levels in 64% of patients with metastatic prostate cancer and elicited an immunological response in 85.7% of patients. In NSCLC, the second vaccination produced a robust TERT-specific immune response and had a favorable tolerance profile (55).

DNA vaccines

Recombinant DNA technology can be used to generate the genome encoding the TERT peptide. These genomes can be inserted onto plasmids and transmitted to antigen-presenting cells, increasing T lymphocyte epitope presentation effectiveness. While INVAC-1 is a plasmid that codes for the inactive version of TERT, phTERT is a DNA-based vaccination that codes for TERT (16). In the HPV-related and melanoma-related tumor models, respectively, the phTERT and INVAC-1 vaccinations reduced tumor growth and extended survival (56).

Small molecule inhibitors

By non-competitively attaching to the active site of TERT, the non-nucleotide small molecule chemical known as BIBR1532 acid specifically suppresses telomerase activity. Despite the positive outcomes of preclinical research on cell lines from breast and prostate cancer (57).

Targeting G-quadruplex

The telomerase enzyme is prevented from accessing the telomeric 3′-overhang by the G-quadruplex. Experimental data indicate that the G-quadruplex structure exists in vivo and in vitro, where it is involved in 3′ end protection (58). The creation of compounds that stabilize G-quadruplex structure is prompted by the importance of G-quadruplex structure in telomere stabilization. 3,6,9-trisubstituted acridine is the trisubstituted acridine BRACO-19.G-quadreplex ligand -3,6-bis(3-pyrrolodinopropionamido) acridine inhibits telomerase access and causes telomere uncapping and telomeric fusion (59). RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl] acridinium methosulfate) is a pentacyclic acridine that is another G4 ligand that may have anticancer properties. Treatment with RHPS4 caused telomere dysfunction, toxicity, and DNA damage signaling in melanoma cells, but not in normal fibroblasts. Teloestatin, a G-quadruplex stabilizing molecule, was isolated from Streptomyces anulatus 3533-SV4 and demonstrated both apoptosis and telomere shortening (60).

Gene therapy

One of the most well-known gene therapy compounds is imetelstat (GRN163L), which has been previously described. A chimera gene, or the coding sequence of a proapoptotic protein regulated by the TERT gene promoter, is one of the alternative tactics. An attenuated adenovirus-5 vector called telomelysine causes cancer cells that overexpress TERT to lyse. Utilizing genetically altered virus vectors that encode a cytotoxic prodrug activating enzyme is a further strategy (61).

Telomerase inhibitors derived from natural products and microbial sources:

It has been determined that natural materials with the ability to suppress telomerase could be used as chemotherapeutic drugs to treat cancer. Polyphenols (curcumin, quercetin, resveratrol, and tannic acid), alkaloids (boldine and berberine), terpenoids (pristimerin and oleanane), and xanthones (gambogic acid and gambogenic acid) are examples of naturally occurring plant chemicals that have telomerase-inhibiting properties (62). Oleic acid is a monounsaturated fatty acid that is found in both vegetable and animal oils. It is categorized as omega-9 and has been shown to inhibit human telomerase (61). Microorganisms called actinomycetes spp. have rings of benzofuran and benzodipyrane, which have telomerase-inhibiting properties. Recently, telomerase inhibitory action of robomycins derived from Streptomyces collinus has been investigated (63).

Targeting telomeric cap

Many studies have shown that TRF1 and TRF2 are overexpressed in a variety of malignancies. TRF1 and TRF2 prevent end-to-end fusion of chromosomes by binding to the telomeric double-stranded 5′-TTAGGG-3′ repeat (64). Because TRF1 and TRF 2 are crucial for genomic stability, it may be more necessary to target them in order to cause genomic instability in malignant cells, which ultimately results in cell death. Considering this, we have demonstrated that focusing on TRF1 and TRF2 in RCC results in both apoptosis and cell cycle arrest (65). The Maria Garcia-Beccaria group has demonstrated that focusing on TRF1 abrogation results in a significant decrease in the quantity and size of malignant lung cancer (66). POT1, stabilizes the telomeric structure by binding to the single strand overhang of the telomeric sequence with a very high degree of sequence specificity. When anti-POT1 siRNAs were used to treat breast cancer cells, the function of POT1 in telomere protection was determined. Treatment with POT1 siRNA causes telomere disruption, activation of apoptosis, and increased expression of p53 and the pro-apoptotic protein Bax (67). Telomere end fusion and chromosomal instability were caused by POT1 gene deletion in mice provides more evidence for POT1’s potential involvement in carcinogenesis. Research has demonstrated that the loss of POT 1 causes a temporary DNA damage response at chromosomal ends (68).

Inhibition of signalling pathways

The MAP kinase-mediated signaling pathways have the potential to activate the hTERT gene. For instance, blocking of this route may be a novel strategy to lower hTERT expression and telomerase activity. EtS and AP-1 may be involved in MAP kinase signaling to the hTERT gene (69). Zheng et al. found that the Tetra-Pt derivative of cisplatin, independent of telomerase, could observably suppress tumor growth in ALT-activated U2OS cancer cells by inhibiting the ALT pathway (70).

Downregulation of TERT expression

Shortening telomere lengths can be accomplished by downregulating TERT expression through the use of gene therapy technology. 5-aza-2′-deoxycytidine (DAC), a DNA demethylating agent, shortened telomeres by suppressing TERT expression, which was brought on by a reduction in c-myc binding to the hTERT promoter (71). The downregulation of hTERT resulted in a notable reduction in telomere length, which in turn inhibited the growth and carcinogenic potential of A549 cancer cells (72). A recombinant retrovirus vector containing the whole hTERT antisense complementary DNA was produced. It is evident that the vector system may suppress telomerase activity and hTERT gene expression, ultimately slowing the growth of the ovarian tumor and extending the mice’s survival period. The ZD55-hTERT and PEGylated carboxymethyl chitosan/calcium phosphate hybrid anionic nanoparticles containing hTERT siRNA have the ability to significantly quiet hTERT, hence impeding the growth of tumors (73).

Active agents in clinical trials

Since 2010, as indicated in (Table 1), several telomere-targeted therapies have been evaluated in clinical trials for a variety of cancer types. Telomere has currently emerged as a promising target in cancer therapy. Drugs targeting telomeres that have been approved in clinical trials primarily fall into two groups: compounds used in chemotherapy and immunotherapy (74). Telomerase-specific oncolytic adenoviruses, like OBP-301 and KH901; hTERT peptide vaccines, like GV1001, UCPVax, VX-001, UV1 and GX301, hTERT peptide, and hTERT and survivin multi-peptide; hTERT DNA vaccines, like INVAC-1, V934/V935 and INO-1400/1401/5401; hTERT mRNA vaccines (75); dendritic cell vaccines, like hTERT RNA transfected DCs and hTERT peptide pulsed DCs; and transgenic lymphocyte immunization vaccines against telomerase (76). Chemotherapeutics are further subdivided between nucleoside analogue 6-thio-2’-deoxyguanosine and telomerase inhibitors like imetelstat and KML-001, which induce telomere dysfunction (43). 6-thio-dG (THIO) induces telomerase mediated telomeric DNA damages that are sensed by dendritic cells and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in tumor-specific CD8+ T cell activation. In addition, 6-thio-dG overcomes resistance to checkpoint blockade in advanced cancer mode (77, 78). Imetelstat was shown in multiple clinical trials to suppress telomerase activity in tumor cells and peripheral blood mononuclear cells (PBMCs), however it had serious adverse effects in children with recurrent central nervous system (CNS) malignancies (76). Imetelstat improved median progression-free survival (PFS) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) (79).

Table 1

Table 1. Clinical trials of telomere-related anti-cancer therapeutics.

Conclusions

This study concludes that understanding of telomere and telomerase structure and function, and of their mechanisms of action, holds the greatest potential for the discovery of novel cancer therapies. Because shelterin and dynamic telomeres, crucial for the survival and proliferation of cancer cells, depend on the modulation of telomerase activity entailing telomerase and shelterin protein interactions and substrate recruitment to the active site of telomerase, this may prove to be a very good strategy. The molecular mechanisms of genetic and epigenetic regulation that activate one of the hallmarks of cancer, human telomerase reverse transcriptase, play very important roles in the initiation of cancer and tumor progression. These features provide a strong foundation for developing targeted therapeutics to treat cancer by targeting specific telomere maintenance mechanisms. Several strategies have been employed in telomere-related therapeutics, such as downregulating TERT expression, reducing telomerase recruitment to telomeres, inducing telomere dysfunction, and interfering with the alternative lengthening of telomeres (ALT) pathway. Several telomere-targeting agents have been developed, including antisense oligonucleotides that block the expression of TERT, the enzyme responsible for telomerase activity; G-quadruplex stabilizers that prevent telomerase from elongating telomeres; small-molecule inhibitors that inhibit telomerase activity or prevent its recruitment to telomeres; and immunotherapies that trigger immune responses against cancer cells by inducing telomere stress. Gene therapy with telomerase promoter-driven suicide genes selectively kills cancer cells overexpressing telomerase, while ALT inhibitors block the alternative lengthening of telomeres pathway used by some cancers. These agents offer the potential for selective, less toxic treatments for cancer, often in combination with other therapies such as chemotherapy or immunotherapy. However, for optimal efficacy, several challenges must be overcome, including tumor heterogeneity, timing of treatment, and potential for side effects. Despite these challenges, telomere-targeting agents represent a promising approach in cancer therapy by directly attacking the mechanisms that allow cancer cells to avoid normal aging processes and continue to proliferate.

Author contributions

TB: Conceptualization, Data curation, Methodology, Project administration, Software, Supervision, Validation, Writing – original draft, Writing – review & editing. MJ: Data curation, Formal analysis, Funding acquisition, Methodology, Writing – original draft, Writing – review & editing. GB: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. MG: Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. GA: Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing. AA: Formal analysis, Funding acquisition, Investigation, Writing – original draft, Writing – review & editing. DA: Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. ZH: Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. ZT: Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. BT: Investigation, Methodology, Project administration, Resources, Software, Writing – original draft, Writing – review & editing. EG: Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing – original draft, Writing – review & editing. TA: Data curation, Formal analysis, Funding acquisition, Investigation, Writing – original draft, Writing – review & editing. GG: Formal analysis, Funding acquisition, Investigation, Methodology, Writing – original draft, Writing – review & editing. BA: Data curation, Methodology, Supervision, Conceptualization, Writing – original draft. DS: Investigation, Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis, Funding acquisition.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

ALT, Alternative Lengthening of Telomeres; ATR, Ataxia Telangiectasia and Rad3-Related; B-Catenin, Beta-Catenin; DAC, 5-Aza-2′-deoxycytidine; hTERT, Human Telomerase Reverse Transcriptase; hTR, Human Telomerase RNA; HLA, Human Leukocyte Antigen; MHC, Major Histocompatibility Complex; NSCLC, Non-Small Cell Lung Cancer; PBMC, Peripheral Blood Mononuclear Cells; POT1, Protection of Telomere 1; RNP, Ribonucleoprotein; RPA, Replication Protein A; RAP1, Repressor/Activator Protein 1; RISC, RNA-Induced Silencing Complex; RNA, Ribonucleic Acid; siRNA, Small Interfering RNA; SS-DNA, Single-Stranded DNA; TERRA, Telomeric Repeat-containing RNA; TIN2, TRF1-Interacting Nuclear Factor 2; TPP1, Telomere Protection Protein 1; TRAP, Telomeric Repeat Amplification Protocol; TRF, Telomere Repeat Binding Factor; TTP, Telomerase Targeted Peptide.

References

1. Srinivas N, Rachakonda S, Kumar R. Telomeres and telomere length: A general overview. Cancers (Basel). (2020) 12(3):558. doi: 10.3390/cancers12030558

PubMed Abstract | Crossref Full Text | Google Scholar

2. Zhang Y, Hou K, Tong J, Zhang H, Xiong M, Liu J, et al. The altered functions of shelterin components in ALT cells. Int J Mol Sci. (2023) 24(23):16830. doi: 10.3390/ijms242316830

PubMed Abstract | Crossref Full Text | Google Scholar

3. Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. (2017) 18:175–86. doi: 10.1038/nrm.2016.171

PubMed Abstract | Crossref Full Text | Google Scholar

4. Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. (2011) 21:349–53. doi: 10.1016/j.semcancer.2011.10.001

PubMed Abstract | Crossref Full Text | Google Scholar

5. Salimi-Jeda A, Badrzadeh F, Esghaei M, Abdoli A. The role of telomerase and viruses interaction in cancer development, and telomerase-dependent therapeutic approaches. Cancer Treat Res Commun. (2021) 27:100323. doi: 10.1016/j.ctarc.2021.100323

PubMed Abstract | Crossref Full Text | Google Scholar

6. Leão R, Apolónio JD, Lee D, Figueiredo A, Tabori U, Castelo-Branco P. Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer. J Biomed Science. (2018) 25:22. doi: 10.1186/s12929-018-0422-8

PubMed Abstract | Crossref Full Text | Google Scholar

7. O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. (2010) 11:171–81. doi: 10.1038/nrm2848

PubMed Abstract | Crossref Full Text | Google Scholar

8. Muraki K, Nyhan K, Han L, Murnane JP. Mechanisms of telomere loss and their consequences for chromosome instability. Front Oncol. (2012) 2:135. doi: 10.3389/fonc.2012.00135

PubMed Abstract | Crossref Full Text | Google Scholar

9. Bonnell E, Pasquier E, Wellinger RJ. Telomere replication: solving multiple end replication problems. Front Cell Dev Biol. (2021) 9:668171. doi: 10.3389/fcell.2021.668171

PubMed Abstract | Crossref Full Text | Google Scholar

10. Episkopou H, Draskovic I, Van Beneden A, Tilman G, Mattiussi M, Gobin M, et al. Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin. Nucleic Acids Res. (2014) 42:4391–405. doi: 10.1093/nar/gku114

PubMed Abstract | Crossref Full Text | Google Scholar

11. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. (2005) 19:2100–10. doi: 10.1101/gad.1346005

PubMed Abstract | Crossref Full Text | Google Scholar

12. Jafri MA, Ansari SA, Alqahtani MH, Shay JW. Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med. (2016) 8:69. doi: 10.1186/s13073-016-0324-x

PubMed Abstract | Crossref Full Text | Google Scholar

13. Ruis P, Boulton SJ. The end protection problem-an unexpected twist in the tail. Genes Dev. (2021) 35:1–21. doi: 10.1101/gad.344044.120

PubMed Abstract | Crossref Full Text | Google Scholar

14. Storchova R, Palek M, Palkova N, Veverka P, Brom T, Hofr C, et al. Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres. Nucleic Acids Res. (2023) 51:1154–72. doi: 10.1093/nar/gkac1269

PubMed Abstract | Crossref Full Text | Google Scholar

15. Rubtsova M, Dontsova O. Human telomerase RNA: telomerase component or more? Biomolecules. (2020) 10:873. doi: 10.3390/biom10060873

PubMed Abstract | Crossref Full Text | Google Scholar

16. Trybek T, Kowalik A, Góźdź S, Kowalska A. Telomeres and telomerase in oncogenesis. Oncol Lett. (2020) 20:1015–27. doi: 10.3892/ol.2020.11659

PubMed Abstract | Crossref Full Text | Google Scholar

17. Shepelev N, Dontsova O, Rubtsova M. Post-transcriptional and post-translational modifications in telomerase biogenesis and recruitment to telomeres. Int J Mol Sci. (2023) 24(5):5027. doi: 10.3390/ijms24055027

PubMed Abstract | Crossref Full Text | Google Scholar

18. Yang R, Han Y, Guan X, Hong Y, Meng J, Ding S, et al. Regulation and clinical potential of telomerase reverse transcriptase (TERT/hTERT) in breast cancer. Cell Commun Signal. (2023) 21:218. doi: 10.1186/s12964-023-01244-8

PubMed Abstract | Crossref Full Text | Google Scholar

19. Dratwa M, Wysoczańska B, Łacina P, Kubik T, Bogunia-Kubik K. TERT-regulation and roles in cancer formation. Front Immunol. (2020) 11:589929. doi: 10.3389/fimmu.2020.589929

PubMed Abstract | Crossref Full Text | Google Scholar

20. Palamarchuk AI, Kovalenko EI, Streltsova MA. Multiple actions of telomerase reverse transcriptase in cell death regulation. Biomedicines. (2023) 11(10):1091. doi: 10.3390/biomedicines11041091

PubMed Abstract | Crossref Full Text | Google Scholar

21. Cong YS, Wright WE, Shay JW. Human telomerase and its regulation. Microbiol Mol Biol Rev. (2002) 66:407–25. doi: 10.1128/MMBR.66.3.407-425.2002

PubMed Abstract | Crossref Full Text | Google Scholar

22. Schrumpfová PP, Fajkus J. Composition and function of telomerase-A polymerase associated with the origin of eukaryotes. Biomolecules. (2020) 10:1425. doi: 10.3390/biom10101425

PubMed Abstract | Crossref Full Text | Google Scholar

23. Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. (1999) 13:817–26. doi: 10.1101/gad.13.7.817

PubMed Abstract | Crossref Full Text | Google Scholar

24. Egan ED, Collins K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol Cell Biol. (2012) 32:2428–39. doi: 10.1128/MCB.00286-12

PubMed Abstract | Crossref Full Text | Google Scholar

25. Hockemeyer D, Collins K. Control of telomerase action at human telomeres. Nat Struct Mol Biol. (2015) 22:848–52. doi: 10.1038/nsmb.3083

PubMed Abstract | Crossref Full Text | Google Scholar

26. Schmidt JC, Cech TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. (2015) 29:1095–105. doi: 10.1101/gad.263863.115

PubMed Abstract | Crossref Full Text | Google Scholar

27. Judasz E, Lisiak N, Kopczyński P, Taube M, Rubiś B. The role of telomerase in breast cancer’s response to therapy. Int J Mol Sci. (2022) 23(21):12844. doi: 10.3390/ijms232112844

PubMed Abstract | Crossref Full Text | Google Scholar

28. Bertorelle R, Rampazzo E, Pucciarelli S, Nitti D, De Rossi A. Telomeres, telomerase and colorectal cancer. World J Gastroenterol. (2014) 20:1940–50. doi: 10.3748/wjg.v20.i8.1940

PubMed Abstract | Crossref Full Text | Google Scholar

29. Parris CN, Jezzard S, Silver A, MacKie R, McGregor JM, Newbold RF. Telomerase activity in melanoma and non-melanoma skin cancer. Br J Cancer. (1999) 79:47–53. doi: 10.1038/sj.bjc.6690010

PubMed Abstract | Crossref Full Text | Google Scholar

30. Samadi FM, Suhail S, Sonam M, Ahmad MK, Chandra S, Saleem M. Telomerase in saliva: An assistant marker for oral squamous cell carcinoma. J Oral Maxillofac Pathol. (2019) 23:187–91. doi: 10.4103/jomfp.JOMFP_83_19

PubMed Abstract | Crossref Full Text | Google Scholar

31. Toupance S, Fattet AJ, Thornton SN, Benetos A, Guéant JL, Koscinski I. Ovarian telomerase and female fertility. Biomedicines. (2021) 9(7):842. doi: 10.3390/biomedicines9070842

PubMed Abstract | Crossref Full Text | Google Scholar

32. Zisuh AV, Han TQ, Zhan SD. Expression of telomerase & its significance in the diagnosis of pancreatic cancer. Indian J Med Res. (2012) 135:26–30. doi: 10.4103/0971-5916.93420

PubMed Abstract | Crossref Full Text | Google Scholar

33. Shay JW. Role of telomeres and telomerase in aging and cancer. Cancer Discovery. (2016) 6:584–93. doi: 10.1158/2159-8290.CD-16-0062

PubMed Abstract | Crossref Full Text | Google Scholar

34. Heaphy CM, Meeker AK. The potential utility of telomere-related markers for cancer diagnosis. J Cell Mol Med. (2011) 15:1227–38. doi: 10.1111/j.1582-4934.2011.01284.x

PubMed Abstract | Crossref Full Text | Google Scholar

35. Piatyszek MA, Kim NW, Weinrich SL, Hiyama K, Hiyama E, Wright WE, et al. Detection of telomerase activity in human cells and tumors by a telomeric repeat amplification protocol (TRAP). Methods Cell Science. (1995) 17:1–15. doi: 10.1007/BF00981880

Crossref Full Text | Google Scholar

36. Herbert BS, Wright WE, Shay JW. Telomerase and breast cancer. Breast Cancer Res. (2001) 3:146–9. doi: 10.1186/bcr288

PubMed Abstract | Crossref Full Text | Google Scholar

37. Yuan X, Larsson C, Xu D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene. (2019) 38:6172–83. doi: 10.1038/s41388-019-0872-9

PubMed Abstract | Crossref Full Text | Google Scholar

38. Lim MCJ, Baird AM, Aird J, Greene J, Kapoor D, Gray SG, et al. RNAs as candidate diagnostic and prognostic markers of prostate cancer-from cell line models to liquid biopsies. Diagnostics (Basel). (2018) 8(3):60. doi: 10.3390/diagnostics8030060

PubMed Abstract | Crossref Full Text | Google Scholar

39. Noureen N, Wu S, Lv Y, Yang J, Alfred Yung WK, Gelfond J, et al. Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation. Nat Commun. (2021) 12:139. doi: 10.1038/s41467-020-20474-9

PubMed Abstract | Crossref Full Text | Google Scholar

40. Baena-Del-Valle JA, Zheng Q, Esopi DM, Rubenstein M, Hubbard GK, Moncaliano MC, et al. MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol. (2018) 244:11–24. doi: 10.1002/path.4980

PubMed Abstract | Crossref Full Text | Google Scholar

41. Sanchini MA, Bravaccini S, Medri L, Gunelli R, Nanni O, Monti F, et al. Urine telomerase: an important marker in the diagnosis of bladder cancer. Neoplasia. (2004) 6:234–9. doi: 10.1593/neo.03433

PubMed Abstract | Crossref Full Text | Google Scholar

42. Eissa S, Swellam M, Ali-Labib R, Mansour A, El-Malt O, Tash FM. Detection of telomerase in urine by 3 methods: evaluation of diagnostic accuracy for bladder cancer. J Urol. (2007) 178:1068–72. doi: 10.1016/j.juro.2007.05.006

PubMed Abstract | Crossref Full Text | Google Scholar

43. Guterres AN, Villanueva J. Targeting telomerase for cancer therapy. Oncogene. (2020) 39:5811–24. doi: 10.1038/s41388-020-01405-w

PubMed Abstract | Crossref Full Text | Google Scholar

44. Shay JW, Wright WE. Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. (2010) 584:3819–25. doi: 10.1016/j.febslet.2010.05.026

PubMed Abstract | Crossref Full Text | Google Scholar

45. Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. (2017) 216:875–87. doi: 10.1083/jcb.201610111

PubMed Abstract | Crossref Full Text | Google Scholar

46. Eckburg A, Dein J, Berei J, Schrank Z, Puri N. Oligonucleotides and microRNAs targeting telomerase subunits in cancer therapy. Cancers (Basel). (2020) 12(9):2337. doi: 10.3390/cancers12092337

PubMed Abstract | Crossref Full Text | Google Scholar

47. Andrews LG, Tollefsbol TO. Methods of telomerase inhibition. Methods Mol Biol. (2007) 405:1–7.

Google Scholar

48. Mender I, Senturk S, Ozgunes N, Akcali KC, Kletsas D, Gryaznov S, et al. Imetelstat (a telomerase antagonist) exerts off−target effects on the cytoskeleton. Int J Oncol. (2013) 42:1709–15. doi: 10.3892/ijo.2013.1865

PubMed Abstract | Crossref Full Text | Google Scholar

49. Dikmen ZG, Gellert GC, Jackson S, Gryaznov S, Tressler R, Dogan P, et al. In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res. (2005) 65:7866–73. doi: 10.1158/0008-5472.CAN-05-1215

PubMed Abstract | Crossref Full Text | Google Scholar

50. Gellert GC, Dikmen ZG, Wright WE, Gryaznov S, Shay JW. Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer. Breast Cancer Res Treat. (2006) 96:73–81. doi: 10.1007/s10549-005-9043-5

PubMed Abstract | Crossref Full Text | Google Scholar

51. Ouellette MM, Wright WE, Shay JW. Targeting telomerase-expressing cancer cells. J Cell Mol Med. (2011) 15:1433–42. doi: 10.1111/j.1582-4934.2011.01279.x

PubMed Abstract | Crossref Full Text | Google Scholar

52. Fan T, Zhang M, Yang J, Zhu Z, Cao W, Dong C. Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduction Targeted Ther. (2023) 8:450. doi: 10.1038/s41392-023-01674-3

PubMed Abstract | Crossref Full Text | Google Scholar

53. Mizukoshi E, Kaneko S. Telomerase-targeted cancer immunotherapy. Int J Mol Sci. (2019) 20(8):1823. doi: 10.3390/ijms20081823

PubMed Abstract | Crossref Full Text | Google Scholar

54. Filaci G, Fenoglio D, Nolè F, Zanardi E, Tomasello L, Aglietta M, et al. Telomerase-based GX301 cancer vaccine in patients with metastatic castration-resistant prostate cancer: a randomized phase II trial. Cancer Immunol Immunother. (2021) 70:3679–92. doi: 10.1007/s00262-021-03024-0

PubMed Abstract | Crossref Full Text | Google Scholar

55. Marshall DJ, San Mateo LR, Rudnick KA, McCarthy SG, Harris MC, McCauley C, et al. Induction of Th1-type immunity and tumor protection with a prostate-specific antigen DNA vaccine. Cancer Immunol Immunother. (2005) 54:1082–94. doi: 10.1007/s00262-005-0687-0

PubMed Abstract | Crossref Full Text | Google Scholar

56. Wang J, Ma L, Chen Y, Zhou R, Wang Q, Zhang T, et al. Immunogenicity and effectiveness of an mRNA therapeutic vaccine for HPV-related Malignancies. Life Sci Alliance. (2024) 7. doi: 10.26508/lsa.202302448

PubMed Abstract | Crossref Full Text | Google Scholar

57. Altamura G, Degli Uberti B, Galiero G, De Luca G, Power K, Licenziato L, et al. The small molecule BIBR1532 exerts potential anti-cancer activities in preclinical models of feline oral squamous cell carcinoma through inhibition of telomerase activity and down-regulation of TERT. Front Vet Sci. (2020) 7:620776. doi: 10.3389/fvets.2020.620776

PubMed Abstract | Crossref Full Text | Google Scholar

58. Bryan TM. G-quadruplexes at telomeres: friend or foe? Molecules. (2020) 25(16):3686. doi: 10.3390/molecules25163686

PubMed Abstract | Crossref Full Text | Google Scholar

59. Burger AM, Dai F, Schultes CM, Reszka AP, Moore MJ, Double JA, et al. The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res. (2005) 65:1489–96. doi: 10.1158/0008-5472.CAN-04-2910

PubMed Abstract | Crossref Full Text | Google Scholar

60. Leonetti C, Amodei S, D’Angelo C, Rizzo A, Benassi B, Antonelli A, et al. Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration. Mol Pharmacol. (2004) 66:1138–46. doi: 10.1124/mol.104.001537

PubMed Abstract | Crossref Full Text | Google Scholar

61. Gomez DL, Armando RG, Cerrudo CS, Ghiringhelli PD, Gomez DE. Telomerase as a cancer target. Development of new molecules. Curr Top Med Chem. (2016) 16:2432–40. doi: 10.2174/1568026616666160212122425

PubMed Abstract | Crossref Full Text | Google Scholar

62. Ganesan K, Xu B. Telomerase inhibitors from natural products and their anticancer potential. Int J Mol Sci. (2017) 19(1):13. doi: 10.3390/ijms19010013

PubMed Abstract | Crossref Full Text | Google Scholar

63. Chen J, Xu L, Zhou Y, Han B. Natural products from actinomycetes associated with marine organisms. Mar Drugs. (2021) 19(11):629. doi: 10.3390/md19110629

PubMed Abstract | Crossref Full Text | Google Scholar

64. Fan HC, Chang FW, Tsai JD, Lin KM, Chen CM, Lin SZ, et al. Telomeres and cancer. Life (Basel). (2021) 11(12):1405. doi: 10.3390/life11121405

PubMed Abstract | Crossref Full Text | Google Scholar

65. Chae M, Lee JH, Park JH, Keum DY, Jung H, Lee Y, et al. Different role of TRF1 and TRF2 expression in non-small cell lung cancers. Onco Targets Ther. (2024) 17:463–9. doi: 10.2147/OTT.S461430

PubMed Abstract | Crossref Full Text | Google Scholar

66. García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, et al. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage. EMBO Mol Med. (2015) 7:930–49. doi: 10.15252/emmm.201404497

PubMed Abstract | Crossref Full Text | Google Scholar

67. Lei M, Podell ER, Cech TR. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol. (2004) 11:1223–9. doi: 10.1038/nsmb867

PubMed Abstract | Crossref Full Text | Google Scholar

68. Wu Y, Poulos RC, Reddel RR. Role of POT1 in human cancer. Cancers (Basel). (2020) 12(10):2739. doi: 10.3390/cancers12102739

PubMed Abstract | Crossref Full Text | Google Scholar

69. Chen H, Li Y, Tollefsbol TO. Strategies targeting telomerase inhibition. Mol Biotechnol. (2009) 41:194–9. doi: 10.1007/s12033-008-9117-9

PubMed Abstract | Crossref Full Text | Google Scholar

70. Zheng XH, Nie X, Fang Y, Zhang Z, Xiao Y, Mao Z, et al. A cisplatin derivative tetra-pt(bpy) as an oncotherapeutic agent for targeting ALT cancer. J Natl Cancer Inst. (2017) 109. doi: 10.1093/jnci/djx061

PubMed Abstract | Crossref Full Text | Google Scholar

71. Ali JH, Walter M. Combining old and new concepts in targeting telomerase for cancer therapy: transient, immediate, complete and combinatory attack (TICCA). Cancer Cell Int. (2023) 23:197. doi: 10.1186/s12935-023-03041-2

PubMed Abstract | Crossref Full Text | Google Scholar

72. Taka T, Huang L, Wongnoppavich A, Tam-Chang SW, Lee TR, Tuntiwechapikul W. Telomere shortening and cell senescence induced by perylene derivatives in A549 human lung cancer cells. Bioorg Med Chem. (2013) 21:883–90. doi: 10.1016/j.bmc.2012.12.020

PubMed Abstract | Crossref Full Text | Google Scholar

73. Qi Z, Mi R. Inhibition of human telomerase reverse transcriptase in vivo and in vitro for retroviral vector-based antisense oligonucleotide therapy in ovarian cancer. Cancer Gene Ther. (2016) 23:36–42. doi: 10.1038/cgt.2015.64

PubMed Abstract | Crossref Full Text | Google Scholar

74. Xu Y, Goldkorn A. Telomere and telomerase therapeutics in cancer. Genes (Basel). (2016) 7(6):22. doi: 10.3390/genes7060022

PubMed Abstract | Crossref Full Text | Google Scholar

75. Ellingsen EB, Aamdal E, Guren T, Lilleby W, Brunsvig PF, Mangsbo SM, et al. Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1: long-term follow-up of three phase I clinical trials. J Immunother Cancer. (2022) 10. doi: 10.1136/jitc-2021-004345

PubMed Abstract | Crossref Full Text | Google Scholar

76. Negrini S, De Palma R, Filaci G. Anti-cancer immunotherapies targeting telomerase. Cancers (Basel). (2020) 12(8):2260. doi: 10.3390/cancers12082260

PubMed Abstract | Crossref Full Text | Google Scholar

77. Mender I, Zhang A, Ren Z, Han C, Deng Y, Siteni S, et al. Telomere stress potentiates STING-dependent anti-tumor immunity. Cancer Cell. (2020) 38:400–11. e6. doi: 10.1016/j.ccell.2020.05.020

PubMed Abstract | Crossref Full Text | Google Scholar

78. Mender I, Gryaznov S, Dikmen ZG, Wright WE, Shay JW. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer discovery. (2015) 5:82–95. doi: 10.1158/2159-8290.CD-14-0609

PubMed Abstract | Crossref Full Text | Google Scholar

79. Chiappori AA, Kolevska T, Spigel DR, Hager S, Rarick M, Gadgeel S, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol. (2015) 26:354–62. doi: 10.1093/annonc/mdu550

PubMed Abstract | Crossref Full Text | Google Scholar

80. clinicaltrials.gov. Trial with telomerase peptide vaccine in combination with temozolomide in patients with advanced Malignant melanoma(2010). Available online at: https://clinicaltrials.gov/ct2/show/NCT01247623?term=NCT01247623&draw=2&rank=1 (Accessed June 18, 2024).

Google Scholar

81. Hunger RE, Kernland Lang K, Markowski CJ, Trachsel S, Møller M, Eriksen JA, et al. Vaccination of patients with cutaneous melanoma with telomerase-specific peptides. Cancer Immunol Immunother. (2011) 60:1553–64. doi: 10.1007/s00262-011-1061-z

PubMed Abstract | Crossref Full Text | Google Scholar

82. Provencio M, Isla D, Sánchez A, Cantos B. Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine. J Thorac Dis. (2011) 3:197–204. doi: 10.3978/j.issn.2072-1439.2011.01.02

PubMed Abstract | Crossref Full Text | Google Scholar

83. clinicaltrials.gov. Imetelstat sodium in treating young patients with refractory or recurrent solid tumors or lymphoma(2011). Available online at: https://clinicaltrials.gov/ct2/show/NCT01273090?term=NCT01273090&draw=2&rank=1 (Accessed June 18, 2024).

Google Scholar

84. Thompson PA, Drissi R, Muscal JA, Panditharatna E, Fouladi M, Ingle AM, et al. A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children’s Oncology Group Phase I Consortium Study (ADVL1112). Clin Cancer Res. (2013) 19:6578–84. doi: 10.1158/1078-0432.CCR-13-1117

PubMed Abstract | Crossref Full Text | Google Scholar

85. Pinto AC, Ades F, de Azambuja E, Piccart-Gebhart M. Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies. Breast. (2013) 22 Suppl 2:S152–5. doi: 10.1016/j.breast.2013.07.029

PubMed Abstract | Crossref Full Text | Google Scholar

86. Kozloff M, Sledge GW, Benedetti FM, Starr A, Wallace JA, Stuart MJ, et al. Phase I study of imetelstat (GRN163L) in combination with paclitaxel (P) and bevacizumab (B) in patients (pts) with locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. (2010) 28:2598. doi: 10.1200/jco.2010.28.15_suppl.2598

Crossref Full Text | Google Scholar

87. Edelman MJ, Lapidus R, Feliciano J, Styblo M, Beumer JH, Liu T, et al. Phase I and pharmacokinetic evaluation of the anti-telomerase agent KML-001 with cisplatin in advanced solid tumors. Cancer Chemother Pharmacol. (2016) 78:959–67. doi: 10.1007/s00280-016-3148-x

PubMed Abstract | Crossref Full Text | Google Scholar

88. clinicaltrials.gov. THIO sequenced with cemiplimab in advanced NSCLC(2022). Available online at: https://clinicaltrials.gov/ct2/show/NCT05208944?term=NCT05208944&draw=2&rank=1 (Accessed June 19, 2024).

Google Scholar

89. Rebucci-Peixoto M, Vienot A, Adotevi O, Jacquin M, Ghiringhelli F, de la Fouchardière C, et al. A phase II study evaluating the interest to combine UCPVax, a telomerase CD4 T(H)1-inducer cancer vaccine, and atezolizumab for the treatment of HPV positive cancers: volATIL study. Front Oncol. (2022) 12:957580. doi: 10.3389/fonc.2022.957580

PubMed Abstract | Crossref Full Text | Google Scholar

90. Haakensen VD, Nowak AK, Ellingsen EB, Farooqi SJ, Bjaanæs MM, Horndalsveen H, et al. NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with Malignant mesothelioma. J Transl Med. (2021) 19:232. doi: 10.1186/s12967-021-02905-3

PubMed Abstract | Crossref Full Text | Google Scholar

91. clinicaltrials.gov. Evaluation of UCPVax plus Nivolumab as second line therapy in advanced non small cell lung cancer (Optim-UCPVax)(2020). Available online at: https://clinicaltrials.gov/ct2/show/NCT04263051?term=NCT04263051&draw=2&rank=1 (Accessed June 20, 2024).

Google Scholar

92. clinicaltrials.gov. Evaluate efficacy, immunological response of intratumoral/intralesional oncolytic virus (OBP-301) in metastatic melanoma(2016). Available online at: https://clinicaltrials.gov/ct2/show/NCT03190824?term=NCT03190824&draw=2&rank=1 (Accessed June 20, 2024).

Google Scholar

93. clinicaltrials.gov. Anticancer therapeutic vaccination using telomerase-derived universal cancer peptides in glioblastoma (UCPVax-Glio)(2020). Available online at: https://clinicaltrials.gov/ct2/show/NCT04280848?term=NCT04280848&draw=2&rank=1 (Accessed June 20, 2024).

Google Scholar

94. Shirakawa Y, Tazawa H, Tanabe S, Kanaya N, Noma K, Koujima T, et al. Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments. Eur J Cancer. (2021) 153:98–108. doi: 10.1016/j.ejca.2021.04.043

PubMed Abstract | Crossref Full Text | Google Scholar

95. Nemunaitis J, Tong AW, Nemunaitis M, Senzer N, Phadke AP, Bedell C, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. (2010) 18:429–34. doi: 10.1038/mt.2009.262

PubMed Abstract | Crossref Full Text | Google Scholar

96. clinicaltrials.gov. INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab (REGN2810) in newly-diagnosed glioblastoma (GBM)(2018). Available online at: https://clinicaltrials.gov/ct2/show/NCT03491683?term=NCT03491683&draw=2&rank=1 (Accessed February 6, 2025).

Google Scholar

97. clinicaltrials.gov. Testing the addition of the anti-cancer viral therapy telomelysin™ to chemoradiation for patients with advanced esophageal cancer and are not candidates for surgery(2020). Available online at: https://clinicaltrials.gov/ct2/show/NCT04391049?term=NCT04391049&draw=2&rank=1 (Accessed June 22, 2024).

Google Scholar

98. Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, et al. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Ther. (2011) 19:990–9. doi: 10.1038/mt.2010.289

PubMed Abstract | Crossref Full Text | Google Scholar

99. Brunsvig PF, Kyte JA, Kersten C, Sundstrøm S, Møller M, Nyakas M, et al. Telomerase peptide vaccination in NSCLC: a phase II trial in stage III patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin Cancer Res. (2011) 17:6847–57. doi: 10.1158/1078-0432.CCR-11-1385

PubMed Abstract | Crossref Full Text | Google Scholar

100. clinicaltrials.gov. Universal cancer peptide-based vaccination in metastatic NSCLC (UCPVax)(2016). Available online at: https://clinicaltrials.gov/ct2/show/NCT02818426?term=NCT02818426&draw=2&rank=1 (Accessed June 22, 2024).

Google Scholar

101. Middleton G, Greenhalf W, Costello E, Shaw V, Cox T, Ghaneh P, et al. Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma. Br J Cancer. (2016) 114:510–8. doi: 10.1038/bjc.2015.468

PubMed Abstract | Crossref Full Text | Google Scholar

102. Vienot A, Jacquin M, Rebucci-Peixoto M, Pureur D, Ghiringhelli F, Assenat E, et al. Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82). BMC Cancer. (2023) 23:710. doi: 10.1186/s12885-023-11065-0

PubMed Abstract | Crossref Full Text | Google Scholar

103. Ellingsen EB, Bounova G, Kerzeli I, Anzar I, Simnica D, Aamdal E, et al. Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination. J Transl Med. (2022) 20:419. doi: 10.1186/s12967-022-03624-z

PubMed Abstract | Crossref Full Text | Google Scholar

104. Vonderheide RH, Kraynyak KA, Shields AF, McRee AJ, Johnson JM, Sun W, et al. Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors. J Immunother Cancer. (2021) 9. doi: 10.1136/jitc-2021-003019

PubMed Abstract | Crossref Full Text | Google Scholar

105. Lilleby W, Gaudernack G, Brunsvig PF, Vlatkovic L, Schulz M, Mills K, et al. Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer. Cancer Immunol Immunother. (2017) 66:891–901. doi: 10.1007/s00262-017-1994-y

PubMed Abstract | Crossref Full Text | Google Scholar

106. clinicaltrials.gov. INO-5401 + INO-9012 in combination with atezolizumab in locally advanced unresectable or metastatic/recurrent urothelial carcinoma(2018). Available online at: https://clinicaltrials.gov/ct2/show/NCT03502785?term=NCT03502785&draw=2&rank=1 (Accessed June 22, 2024).

Google Scholar

107. Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Fang HB, Cai L, et al. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood. (2011) 117:788–97. doi: 10.1182/blood-2010-08-299396

PubMed Abstract | Crossref Full Text | Google Scholar

108. Teixeira L, Medioni J, Garibal J, Adotevi O, Doucet L, Durey MD, et al. A first-in-human phase I study of INVAC-1, an optimized human telomerase DNA vaccine in patients with advanced solid tumors. Clin Cancer Res. (2020) 26:588–97. doi: 10.1158/1078-0432.CCR-19-1614

PubMed Abstract | Crossref Full Text | Google Scholar

109. Jähnisch H, Füssel S, Kiessling A, Wehner R, Zastrow S, Bachmann M, et al. Dendritic cell-based immunotherapy for prostate cancer. Clin Dev Immunol. (2010) 2010:517493. doi: 10.1155/2010/517493

PubMed Abstract | Crossref Full Text | Google Scholar