Novel anticancer therapeutics targeting telomerase

Ruden, Maria; Puri, Neelu

doi:10.1016/j.ctrv.2012.06.007

Cited by 276 publications

(296 citation statements)

References 102 publications

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“…Several strategies of therapeutic telomerase inhibition, including small molecular inhibitors, immunotherapy, gene therapy, and telomere-and telomerase-associated proteins, in different cancers have entered clinical trials (34). The telomerase protein is also associated with other biological activities that include enhanced cell proliferation, inhibition of apoptosis, and regulation of DNA damage response and cellular proliferative life span that could be affected by the promoter mutations (35).…”

Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda

Hosen

Verdier

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

291

341

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The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions −124 and −146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.TERT mutations | cancer genetics | transcription factors | noncoding mutations | reporter assays T he human telomerase reverse transcriptase (TERT) gene encodes the catalytic reverse transcriptase subunit of telomerase that maintains telomere length (1). Increased telomerase activity is perceived to be one of the hallmarks of human cancers, and the transcriptional regulation of the TERT gene is the major cause of its cancer-specific activation (2, 3). The TERT promoter has been shown to be the most important element of telomerase expression because it harbors binding sites for numerous cellular transcriptional activators and repressors that directly or indirectly regulate the gene expression (4). In addition, the high GC content around the transcription start site of the TERT promoter confers epigenetic regulation through methylation and chromatin remodeling (5, 6).We previously described a high-penetrant disease segregating single-nucleotide germ-line mutation in the TERT promoter in a large melanoma family (7). The A > C (T > G) mutation at position −57 bp (from the ATG start site; Chr 5:1295161 hg19 coordinate) resulted in creation of a new binding motif GGAA/T for E-twenty six (Ets) transcription factors and a general binding CCGGAA/T motif for ternary complex factors (TCF) (8). Simultaneous screening of the TERT promoter for somatic mutations...

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Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Rachakonda

Hosen

Verdier

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

291

341

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“…Owing to limited numbers of events in the set of patients included in this study, we could not determine whether the mutations influence melanoma-specific survival or recurrence. Strategies based on therapeutic inhibition of telomerase that include small molecular inhibitors, immunotherapy, gene therapy, telomere and telomerase proteins are already part of clinical trials 44 . Further research will determine usefulness of the TERT promoter mutations in the context of melanoma treatment where strategies based on BRAF inhibitors have shown a vast potential despite persistent issue of resistance 45 .…”

Section: Tert Promoter Mutationsmentioning

confidence: 99%

Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma

Nagore²,

et al. 2014

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We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both intermittently and chronically sun-exposed sites than non-exposed sites and tend to co-occur with BRAF and CDKN2A alterations. The association with parameters generally connected with poor outcome, coupled with high recurrence and mechanistic relevance, raises the possibility of the eventual use of TERT promoter mutations in the disease management.

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“…BIBR1532 is one of the most promising TERT specific-inhibitors to date. Other small synthetic molecules-G-quadruplex ligands, such as BRACO19, RHSP4 and telomestatin-are promising drugs that can be used for TERT targeting therapies [103]. However, clinical testing of some of these molecules has been hampered due to the toxic characteristics of the compounds [82].…”

Section: Telomerase As a Therapeutic Targetmentioning

confidence: 99%

“…Different peptides have been used to induce anti-TERT immune response [13] and vaccination using the I540-548 peptide showed anti-tumour responses in cancer [122]. Several preclinical studies using TERT peptides are being conducted (reviewed in [103]). GV-1001, GRNVAC 1 and Vx-001 are the most promising vaccines available to date.…”

Section: Telomerase As a Therapeutic Targetmentioning

confidence: 99%

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

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Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the "alternative mechanism of telomere lengthening" (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and nonneoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.

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Novel anticancer therapeutics targeting telomerase

Cited by 276 publications

References 102 publications

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

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