Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor

Hu, Yafang; Bobb, Daniel; Lu, Yunbiao; He, Jie; Dome, Jeffrey S.

doi:10.1016/j.cancergen.2014.09.002

Cited by 14 publications

(4 citation statements)

References 47 publications

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“…Imetelstat alone significantly decreased telomere length through hTERT inhibition and increased cell death of human myeloma and pancreatic cancer cells in an in vitro model [63,86]. Xenograft murine models showed similar results for both myeloma and malignant rhabdoid tumor cells, demonstrating telomere shortening, decreased growth, and increased cell death [86,87]. Additionally, Imetelstat has exhibited anti-metastatic properties in mouse models of lung cancer [88,89].…”

Section: Oligonucleotidesmentioning

confidence: 87%

Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Eckburg

Dein

Berei

et al. 2020

Cancers

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Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

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Section: Oligonucleotidesmentioning

confidence: 87%

Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Eckburg

Dein

Berei

et al. 2020

Cancers

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“…GRN163L can induce DDR by upregulating H2AX. In an experiment using a malignant rhabdoid tumor cell to evaluate the effect of GRN163L, it was found that intracellular expression of H2AX was upregulated, which caused the activation of DDR . Telomerase is not only important for the immortalization of tumor cell, but it also plays a key role in the metastasis of the tumor cell; GRN163L appears to be resistant to tumor metastasis.…”

Section: Oligonucleotides Targeting Telomeres and Telomerasementioning

confidence: 99%

Therapeutic strategies for targeting telomerase in cancer

Chen

Tang

Shi

et al. 2019

Medicinal Research Reviews

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Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

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“…Activation of DNA damage responses was observed in malignant rhabdoid tumor cells treated with GRN163L as demonstrated by γH2AX foci formation, phosphorylation of ATM, and phosphorylation of TP53. Additionally, in mouse xenograft tumor models, there was a 40–50% reduction in tumor growth upon treatment with GRN163L for 50 days [ 21 ].…”

Section: Grn163lmentioning

confidence: 99%

“…However, inhibition of telomerase as a clinical approach is complicated by the lengthy timeframe before inactivation of telomerase leads to critical telomere shortening. In the case of GRN13L, studies have shown that telomerase inhibition induces anticancer effects in cancer cells after weeks of treatment [ 19 , 21 ]. Additionally, the effects of miRNAs that reduce telomerase activity in stem cells has not yet been explored and requires further study.…”

Section: Mirnas Targeting Telomerasementioning

confidence: 99%

Oligonucleotides Targeting Telomeres and Telomerase in Cancer

et al. 2018

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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.

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Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor

Cited by 14 publications

References 47 publications

Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy

Therapeutic strategies for targeting telomerase in cancer

Oligonucleotides Targeting Telomeres and Telomerase in Cancer

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