Information about imetelstat: the first clinical stage telomerase inhibitor

Pre-clinical research

There exists a history of preclinical research on telomerase and imetelstat, ignited after the discovery of telomerase by Carol Greider and Elisabeth Blackburn in 1984. This section provides you with  an archive of past and present scientific research, including links to papers, reports, presentations and other information.


Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells

K.M. Burchett et al (2017)

Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres.

Results from this work suggest that inhibitors of telomerase and poly(ADP-ribose) polymerases can cooperate to limit the lifespan of pancreatic cancer cells.

(Published: Oncotarget, July 20, 2017)

Telomerase Inhibition Impairs Self-Renewal of ß-Catenin Activated Myeloproliferative Neoplasm Progenitors

W. Ma et al (2017)

Chronic phase myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML) and myelofibrosis (MF), arise from hematopoietic stem cells. We performed progenitor RNA sequencing (RNA-seq), stromal co-cultures and humanized MPN progenitor primagraft studies to investigate the ability of imetelstat to selectively inhibit malignant progenitor self-renewal at doses that spare normal progenitors as well as to determine the mechanism of action.

Niche responsive interactions between the telomerase complex and the Wnt/b-catenin self-renewal pathway sensitize b-catenin activated MPN progenitors to imetelstat in both in vitro and in vivo humanized pre-clinical MPN mouse models thereby providing a strong rationale for studies assessing eradication of malignant progenitors using imetelstat.

(ASH2017, abstract 2860)

Integrated Molecular Analysis Identifies Replicative Stress As Sensitizer to Imetelstat Therapy in AML

C. Bruedigam et al (2017)


In summary, imetelstat prolonged overall survival in a large cohort of AML PDX. In 57% (17 out of 30 individual AML patient samples), sustained responses to imetelstat were associated with marked improvements in survival and a baseline replicative stress-annotated transcriptional signature. The rational sequencing of standard induction chemotherapy to induce replicative stress provides proof-of-concept to sensitize imetelstat-resistant AML patient samples and suppress expansion and prevent relapse in AML.

(ASH2017, abstract 798)

Imetelstat, a Telomerase Inhibitor, Is Capable of Depleting Myelofibrosis Hematopoietic Stem Cells and Progenitor Cells

X. Wang et al (2017)

Treatment of myelofibrosis (MF) patients with imetelstat (Imet), a telomerase inhibitor, has been reported to lead to clinical, morphologic and molecular remissions in a subset of patients (Tefferi A, et al. N Engl J Med. 2015; 373:908), suggesting that Imet has disease-modifying activity.

These findings suggest that Imet is capable of selectively promoting apoptosis and inhibiting the proliferation of phenotypically and functionally defined MF but not normal HSCs/HPCs. Imet, therefore, represents a potentially promising drug for the treatment of MF which appears to affect primitive MF HSCs.

(ASH2017, abstract 1654)

Transient telomerase inhibition alters cell cycle kinetics

Connor A. H. Thompson et al (2017)

Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear human chromosomes and contributes to proper chromosomal capping function. Formation of the telomere-loop (T-loop), an obligate step before cell division can proceed, requires the generation of a 3′-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, we discover telomerase activity is critical for efficient cell cycle progression using transient chemical inhibition by the telomerase inhibitor imetelstat.

(Source: BioRxiv, Cold Spring Harbor Laboratory)

Treating Cancer by Targeting Telomeres and Telomerase

M. Invancich et al (Antioxidants, 2017)

Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer.

Currently there is a multitude of drugs designed to directly inhibit telomerase. GRN163L, also called Imetelstat, has been one of the most widely developed and is arguably the most successful. GRN163L is a 13-mer oligonucleotide that acts as a direct telomerase inhibitor by antagonistically binding to the RNA template of telomerase (hTR). Preclinical studies utilizing GRN163L have shown effective inhibition of telomerase. Treatment on breast cancer cells demonstrated a reduction in cell tumorigenicity and invasiveness.

Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia

J. Rusbuldt et al (AACR, 3 April 2017)

Acute myeloid leukemia (AML) is an aggressive cancer with limited treatment options outside of chemotherapy. Improved therapies with novel mechanisms of action are desperately needed to fill this need. 

ML cell lines and AML patient’s PBMC samples were treated with imetelstat or venetoclax alone, or in combination. A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit.

Conclusions: To our knowledge, this is the first investigation combining imetelstat with venetoclax in AML, and the results demonstrated a synergistic effect on induction of apoptosis in cell lines and patient samples in vitro, which translated into prolonged survival in xenograft models, thus providing a strong rationale for clinical exploration of this combination.

link to poster:

Targeting telomerase with radiolabeled inhibitors

Ph. Waghorn et al (European Journal of Medicinal Chemistry, 5 January 2017)

The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, 123I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An 123I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC50 of 1.58 μM (MST-312 IC50: 0.23 μM). Clonogenic assays showed a dose dependant effect of 123I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435.

Systematic analysis of telomere length and somatic alterations in 31 cancer types

R. Verhaak et al (Nature Genetics, 30 January 2017)

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat–containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations.

Telomere Length Linked to Genomic Alterations in 31 Cancers

Genomeweb, 30 January 2017

NEW YORK (GenomeWeb) – Cancer cells use a variety of mechanisms to survive cellular crisis, including through telomere maintenance processes. By activating telomerase, cancer cells can counteract telomere shortening, and therefore avoid tumor-suppressing senescence and crisis.

In a paper published today in Nature Genetics, a team led by researchers at the Jackson Laboratory and the University of Texas MD Anderson Cancer Center showed the links between telomerase activity, genomic abnormalities, and telomere length in 31 different cancer types. They found that telomeres were shorter in tumors than in normal tissues, and longer in sarcomas and gliomas than in other cancers.

"It has been proposed that up to 90 percent of human cancers reactivate telomerase. ./. Our results suggested a positive correlation between TERT expression and telomerase activity, corroborating recent findings in bladder cancer"

Telomerase antagonist imetelstat increases radiation sensitivity in esophageal squamous cell carcinoma

Xuping Wu et al (Oncotarget, January 2017)

The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy.


Telomerase in hematologic malignancies

C. Bruedigam, S.Lane (, Wolters Kluwer Health, July 2016)

Telomerase inhibition has shown remarkable efficacy in myeloid malignancies, and current and future
preclinical and clinical studies are necessary to comprehensively investigate its underlying mechanism of action. Future work should identify the potential genetic susceptibilities to telomerase inhibition therapy, and evaluate rational combinations of telomerase inhibitors with chemotherapy and other novel agents.
Robust preclinical evaluation is essential to best translate these new agents successfully into our clinical treatment algorithm for myeloid and other blood cancers.

In this review, we detail the background biology on telomere maintenance in health and disease, then concentrate on the preclinical and clinical development behind targeting telomerase in blood cancers.

Telomerase Inhibition with Imetelstat Eradicates β-catenin Activated Blast Crisis Chronic Myeloid Leukemia Stem Cells

Wenxue Ma et al, ASH 2016 (Abstract #3065)

Academic scientists presented a preliminary investigation into the potential impact of imetelstat on leukemia stem cells in non-clinical models of chronic myeloid leukemia (CML) in blast crisis. The preclinical data suggest that imetelstat plus dasatinib, a standard treatment for CML, may inhibit self-renewal of blast crisis cells in vitro compared with normal bone marrow progenitors. In mouse xenograft models of blast crisis CML, imetelstat treatment reduced the number of leukemia progenitor cells detected in bone marrow and decreased expression of β-catenin, which is believed to be required for the self-renewal of leukemic stem cells in CML. This is the first report of data to suggest that imetelstat might inhibit proliferation of malignant progenitors in CML.

Researchers uncover key mechanisms of cancer, aging and inflammation

(Medical Press, 7 November 2016)

A team of University of Pittsburgh researchers has uncovered new details about the biology of telomeres, "caps" of DNA that protect the tips of chromosomes and play key roles in a number of health conditions, including cancer, inflammation and aging. The new findings were published today in the journal Nature Structural and Molecular Biology.

Telomerase Inhibition with Imetelstat Eradicates β-Catenin Activated Blast Crisis Chronic Myeloid Leukemia Stem Cells

Wenxue Ma et al (ASH2016, abstract 93873)

Niche responsive interactions between the telomerase complex and the Wnt/b-catenin self-renewal pathway sensitize b-catenin activated LSC to imetelstat in both in vitro and in vivo humanized pre-clinical BC CML models thereby providing a strong rationale for LSC eradication trials involving imetelstat.

The Preclinical Efficacy of a Novel Telomerase Inhibitor, Imetelstat, in AML - a Randomized Trial in Patient-Derived Xenografts

Claudia Braudigam, Steven Lane et al (ASH2016, abstract 96048)

Imetelstat demonstrates efficacy in a significant proportion of AML PDX (60%, 9 out of 15 individual AML patient samples). Robust responses to imetelstat were associated with favourable cytogenetic risk groups and mutations in pathways controlling DNA damage. The effects on normal human hematopoiesis were modest and predominantly seen in the B-lymphocyte lineage with relative preservation of myeloid and stem cell populations. These data build on previously published preclinical work conducted in patient-derived models of AML and suggest potential application of imetelstat in the treatment of AML.

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies

Jerry W. Shay et al (Genome Medicine, 2016)

Imetelstat has been extensively evaluated for its activity and efficacy against multiple cancer cell lines and in mouse xenograft models in preclinical studies. Imetelstat demonstrated potent inhibitory action against telomerase, causing shortening of telomeres in a large spectrum of cancer cell lines derived from tumors of the bladder, breast, lung, liver, prostrate and pancreas. In vivo preclinical studies in mouse models of human tumor xenografts showed that the compound was well tolerated and highly efficacious in inducing telomerase inhibition, leading to reduced tumor growth, prevention of metastasis, and sensitization of tumors to standard chemotherapy. Imetelstat was also found to efficiently prevent glioblastoma tumor growth in a xenograft model by crossing the blood–brain barrier, probably owing to its highly lipophilic nature. Additionally, simultaneous suppression of homologous recombination and telomerase activity in a mouse model of Barrett’s adenocarcinoma with the combination of nilotinib (tyrosine kinase inhibitor) and imetelstat was reported to be more effective compared to either compound alone.

Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner

Robin E. Frink et al (Oncotarget, 2016)

Telomerase was evaluated as a therapeutic oncotarget by studying the efficacy of the telomerase inhibitor imetelstat in non-small cell lung cancer (NSCLC) cell lines to determine the range of response phenotypes and identify potential biomarkers of response.


Continuous long-term treatment with imetelstat resulted in sustained telomerase inhibition, progressive telomere shortening and eventual growth inhibition in a telomere-length dependent manner. Cessation of imetelstat therapy before growth inhibition was followed by telomere regrowth. Likewise, in vivo imetelstat treatment caused tumor xenograft growth inhibition in a telomere-length dependent manner. We conclude from these preclinical studies of telomerase as an oncotarget tested by imetelstat response that imetelstat has efficacy across the entire oncogenotype spectrum of NSCLC, continuous therapy is necessary to prevent telomere regrowth, and short telomeres appears to be the best treatment biomarker.

Epigenetic landscape of the TERT promoter: a potential biomarker for high risk AML/MDS

Xin Zhao et al (British Journal of Haematology, 19 July 2016)

Although recent observations implicate the importance of telomerase activity in acute myeloid leukaemia (AML), the roles of epigenetic regulations of the TERT gene in leukaemogenesis, drug resistance and clinical prognosis in AML are not fully understood.  Prognostic impact of methylation status of the upstream TERT promoter region was assessed by the Kaplan–Meier method. The activity of the telomerase inhibitor, imetelstat, was measured using leukaemia cell lines. The TERTpro/Ex1 region was highly methylated in all cell lines and primary leukaemia cells showed diverse methylation profiles. Most cases showed hypermethylated regions at the upstream TERTpro/Ex1 region, which were associated with inferior patient survival. TERTpro/Ex1 methylation status was correlated with the cytotoxicity to imetelstat and its combination with hypomethylating agent enhanced the cytotoxicity of imetelstat. AML cell lines and primary blasts harbour distinct TERTpro/Ex1 methylation profiles that could serve as a prognostic biomarker of AML. However, validation in a large cohort of patients is necessary to confirm our findings.

Two Poster Presentations about imetelstat from AACR 2016 now available

The first poster presentation described results that treating acute myeloid leukemia (AML) cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies. The second poster presentation described results from non-clinical studies that provide further evidence of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials.

The non-clinical studies were conducted by scientists at Janssen Research & Development, LLC and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. The poster presentations are available on Geron’s website at 

Poster 2731 (Rusbuldt et al) - Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

Poster 2732 (Baerlocher et al) - Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors

Human telomerase RNA component (hTR/TERC) is consistently overexpressed in prostate cancer, required for cell proliferation and is positively regulated by MYC

Javier A. Baena Del Valle et al (2016)

Telomerase activity (TA) is increased in most human cancers (80 - 90%) as a mechanism to maintain telomere function, yet the complex regulatory mechanisms driving TA in different cancer types remain obscure. We report consistent overexpression of TERC in PIN and PCa and show the first evidence of MYC regulation of TERC. These studies suggest an important role for MYC-regulated TERC overexpression in human prostate cancer development and progression. Further studies are required to better understand the functional roles of TERC (e.g. TA mediated vs. other activity) in carcinogenesis of the prostate and other organ sites and its regulation by MYC.

(AACR, Late Breaking Abstract LB-160), 18 April 2016)

Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

J. Rusbuldt et al (2016)

Decitabine (DAC) and azacitidine (AZA) are DNA methyltransferase inhibitors (DNMTIs) used in the treatment of AML. Combining imetelstat and DNMTI may be an improved treatment option for AML. We investigated effects of DAC and AZA on hTERT expression and cell viability in AML cell lines OCI-AML3 and OCI-AML5, and evaluated growth inhibition when combined with imetelstat. Dose-dependent synergistic activity was demonstrated for DAC followed by imetelstat: OCI-AML3 cell viability changed from 95% with DAC to 61% and 10% after 2 and 4 weeks of imetelstat, respectively; OCI-AML5 cell viability changed from 46% with DAC to 6% and 1% after 2 and 4 weeks of imetelstat, respectively.

(AACR, Abstract 2731, Tuesday, 19 April 2016, co-authered by Janssen Research & Development)


Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer

S. Heeg (4 December 2015)

Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities.

New surprises from an old favourite: The emergence of telomerase as a key player in the regulation of cancer stemness

K. Teralı, A. Yilmazer (2015)

• Telomerase has the capacity to regulate numerous cancer-promoting genes and pathways.
• A mechanistic explanation for the regulatory role of telomerase in cancer stem cells is provided.
• Telomerase contributes to tumorigenesis via the acquisition and retention of cancer stemness.
• There is a positive feedback loop between a number of oncoproteins/oncogenic pathways and TERT.
• Telomerase-focused therapies hold the promise of eradicating cancer stem cells.


Variations in telomere maintenance and the role of telomerase inhibition in gastrointestinal cancer

S. Heeg, Dovepress (October 2015)

Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. There are two known mechanisms to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called ALT. While 85% of all human tumors show reactivation of telomerase, the remaining 15% are able to maintain telomeres via ALT. The therapeutic potential of telomerase inhibitors is currently investigated in a variety of human cancers. Gastrointestinal tumors are highly dependent on telomerase as a mechanism of telomere maintenance, rendering telomeres as well as telomerase potential targets for cancer therapy. This article focuses on the molecular mechanisms of telomere biology and telomerase activation in gastrointestinal cancers and reviews strategies of telomerase inhibition and their potential therapeutic use in these tumor entities.

The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis

Chunli Zhang et al (2015)

Telomeres are essential for chromosomal integrity and stability. Shortened telomere length (TL) has been associated with risk of cancers and aging-related diseases. Several studies have explored associations between TL and cancer prognosis, but the results are conflicting. Thirty-three articles containing forty-five independent studies were ultimately involved in our meta-analysis, of which twenty-seven were about overall cancer survival and eighteen were about cancer progression.

Short TL demonstrated a significant association with poor cancer survival, suggesting the potential prognostic significance of TL. Additional large well-designed studies are needed to confirm our findings.

(PLoS One. 2015; 10(7): e0133174. Published online 2015 Jul 15)

Study reveals key structure in telomerase enzyme, a target for cancer drugs

University of California-Santa Cruz (October 5, 2015)

Over-activation of telomerase in 90 percent of malignant tumors has made the unusual enzyme a prime target for drug development efforts

Summary: Researchers have determined the structure of a key part of the enzyme telomerase, which is active in most cancers and enables cancer cells to proliferate indefinitely. The new findings reveal how the enzyme carries out a crucial function involved in protecting the ends of chromosomes.

Michael Stone, associate professor of chemistry and biochemistry at UC Santa Cruz and senior author of the paper: "What makes this interesting for rational drug design is that template boundary definition is a very specific feature of telomerase. Our cells are full of other kinds of polymerase enzymes, so it's important to design a drug that targets only telomerase."

Dysregulation of shelterin factors coupled with telomere shortening in Philadelphia chromosome negative myeloproliferative neoplasms

Jenny Dahlström et al (Haematologica, 2015)

Telomere dysfunction is an early event triggering genomic instability in tumorigenesis. MPNs exhibit genetic alterations with an indolent clinical course.

In summary, we found a significantly reduced TL in granulocytes from patients with MPNs compared to healthy controls. These results collectively reveal widespread dysregulation of shelterin factors in MPNs. The abnormal expression of shelterin factors may contribute to accelerated telomere erosion, thereby driving genetic aberrations and pathogenesis of MPNs. Recently, imetelstat, a small oligonucleotide that mimics telomeric DNA sequences and thereby targets telomere structure and telomerase activity, has been used to treat MPNs and the efficacy is very promising. Given the present finding, it is worth investigating whether expression changes in shelterin proteins may predict MPN patient response to imetelstat treatment or have other therapeutic implications.

Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides

A. Muñoz-Alarcóet al (2015)

At present, there are several therapeutic approaches for targeting telomerase in tumors. One in particular, currently undergoing clinical trials, is based on synthetic lipid-modified oligonucleotide antagonists aimed at inhibiting the ribonucleoprotein subunit of human telomerase. Noncovalent complexation strategies for cell-penetrating peptide (CPP)-mediated delivery present an option to circumvent the need for potency-reducing modifications, while allowing for a highly efficient uptake, and could significantly improve the efficiency of telomerase-targeting cancer therapeutics.

(PubMed, Dec. 2015)

Telomerase Activity and Telomere Length in Human Benign Prostatic Hyperplasia Stem-like Cells and Their Progeny Implies the Existence of Distinct Basal and Luminal Cell Lineages

Jayant K. Rane et al (2015)

We investigated the telomere biology of cell subpopulations from BPH patients undergoing transurethral resection of prostate (TURP). Measurement of TERC, TERT, and telomerase activity revealed that only the epithelial stem-like and progenitor fractions expressed high levels of telomerase activity and individual enzyme components. 

We unexpectedly found an enzyme called telomerase in the cells that maintain benign prostatic hyperplasia (BPH), suggesting that telomerase inhibitors could be used to alleviate BPH symptoms. In benign prostatic hyperplasia (BPH), a small population of basal cells expresses high levels of telomerase. Basal and luminal cells can proliferate independently, implying distinct basal and luminal lineages and suggesting that telomerase-blocking drugs could inhibit epithelial hyperproliferation in BPH.

Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice

A. Raval et al (2015)

Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC), aplastic anemia (AA) and myelodysplastic syndromes (MDS). We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. -/- These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.

Potential paediatric interest of imetelstat suggested by PDCO

European Medicins Agency, Paediatric Committee (PDCO) Minutes for the meeting on 15 - 17 July 2015

Summary of committee discussion:
The applicability of the class waiver to the planned therapeutic indication was confirmed. Potential paediatric interest of this medicine suggested by PDCO:
myelodysplastic syndromes, acute myeloid leukaemia,neuroblastoma, Wilms tumour, hepatoblastoma,Ewing sarcoma and central nervous system tumours.

(Rapporteur: Sylvie Benchetri)

Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis.

A. Valentijn et al (2015)

The observed effects of telomerase inhibition in vitro on epithelial cell proliferation, suggest that telomerase might be an attractive target in developing new therapies for proliferative disorders of the endometrium, such as endometriosis.

Telomere and Telomerase: From Discovery to Cancer Treatment

A. Rezaeifar et al. (2015)

Increased telomerase activity provides cancer cells with unlimited proliferative potential and is one of the hallmarks of cancer. This article provides a basic understanding of telomere and telomerase in cancer and summarizes some potential therapeutic approaches used for strategic targeting of the telomerase enzyme (including imetelstat).

About 90% of cancers need a high level of this enzyme to continue cell multiplication. Since this enzyme set is absent in normal cells, or present at a very low level, use of telomerase inhibitors cannot have significant effects on normal cells. Conclusion: since telomerase is expressed in 90% of cancer cells, its inhibition can be considered as a goal of cancer treatment.

(Gene, Cell and Tissue)

Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma

D. Poncet et al (2015)

Glioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. We used a murine orthotopic model of human GBM and μMRI imaging to evaluate the efficacy of Imetelstat alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase.

The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

Y. Hu et al. (2015)

This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy.

The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells

J.E. Koziel et al. (2015)

Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of HER2(+) breast cancer cell lines. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC populatio

Telomere changes predict cancer

Northwestern University (2015)

A distinct pattern in the changing length of blood telomeres, the protective end caps on our DNA strands, can predict cancer many years before actual diagnosis, according to a new study from Northwestern Medicine in collaboration with Harvard University.

Lifang Hou, MD, PhD, the lead study author: "We found cancer has hijacked the telomere shortening in order to flourish in the body. Because we saw a strong relationship in the pattern across a wide variety of cancers, with the right testing these procedures could be used to eventually diagnose a wide variety of cancers.”

Role for telomerase in pulmonary hypertension

N. Mouraret et al. (2015)

Marked TERT expression or activity was found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT(+) mice), chiefly within PA-SMCs. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. Telomerase exerts telomere-independent effects on PA-SMC growth in PH and may constitute a treatment target for PH.

Identification of human telomerase assembly inhibitors enabled by a novel method to produce hTERT

G. Kellerman et al (2015)

Telomerase is the enzyme that maintains the length of telomeres. Despite its significance as an almost universal cancer target, the understanding of the structure of telomerase and the optimization of specific inhibitors have been hampered by the limited amount of enzyme available. Here, we present a breakthrough method to produce unprecedented amounts of recombinant hTERT and to reconstitute human telomerase with purified components. The novel system presented here may accelerate the understanding of human telomerase assembly and facilitate the discovery of potent and mechanistically unique inhibitors.


Inhibition of Telomerase with Imetelstat is detrimental to Leukemia Stem Cells in Acute Myeloid Leukemia (AML)

C. Bruedigam et al. (2014)

Although most patients respond to induction chemotherapy, the majority will relapse and eventually die of their disease (5-year overall survival: 40-50% for patiënts < 60 years; 10% for patiënts > 60 years of age).

Novel inhibitors of telomerase have recently entered clinical trials for a variety of malignancies, including imetelstat, a competitive inhibitor that binds to the RNA template (TERC) of the telomerase holoenzyme. This study demonstrates the efficacy of pharmacologic inhibition of telomerase using imetelstat in human AML and proposes a novel paradigm of AML therapy that is to delay or prevent relapse by targeting AML stem cells in vivo. (Poster, ASH2014)

Effects of Imetelstat on the Stem Cells of Patients with Myelofibrosis

X. Wang et al. (2014)

Imetelstat at the doses studied has minimal effects on normal CB hematopoiesis. Bycontrast, Imetelstat is capable of selectively inhibiting the proliferation of phenotypically and functionally defined MF hematopoietic stem cells and myeloid progenitor cells through promoting their apoptosis. (Mount Sinai School of Medicin)

Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A

R. Gupta et al. (2014)

Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

Full study here

Researchers uncover new cancer cell vulnerabilities

Yale News (2014)

Yale School of Medicine and Yale Cancer Center researchers have uncovered a genetic vulnerability of cancer cells that express telomerase — an enzyme that drives their unchecked growth — and showed that telomerase-expressing cells depend upon a gene named p21 for their survival.

Authors found that simultaneous inhibition of both telomerase and p21 inhibited tumor growth in mice. The telomerase enzyme is overexpressed in over 90% of human cancers, but not in normal cells, and expression of telomerase is necessary to initiate and promote cancer growth. In this study, the Yale team, led by first author Romi Gupta and corresponding author Narendra Wajapeyee of the Department of Pathology, showed how new pharmacological drug combinations can be applied to simultaneously target both telomerase and p21 to induce cell death in telomerase-expressing cancer cells.

New drug breakthrough shows promise for AML patients

S. Lane (2014)

A researcher funded by the Leukaemia Foundation of Queensland, Dr Steven Lane, has been exploring a new drug that looks to be highly effective against acute myeloid leukaemia (AML) and may prevent patients relapsing.

(video interview)

Geron Announces Publication of Preclinical Data on Imetelstat Activity in Acute Myelogenous Leukemia

MENLO PARK, Calif., December 4, 2014 - Geron Corporation (Nasdaq: GERN) today announced the publication of preclinical data demonstrating activity of the company's telomerase inhibitor drug, imetelstat, on leukemic stem cells from acute myelogenous leukemia (AML). In addition, the preclinical study showed the role of telomerase in AML disease initiation and progression. These data provide preclinical proof-of-concept to support clinical development of imetelstat in AML.

Telomerase Inhibition Effectively Targets Mouse and Human AML Stem Cells and Delays Relapse following Chemotherapy

S. Lane et al. (2014)

Telomerase deficiency eradicates LSC function upon enforced replication. Terc−/− LSCs are eradicated via cell-cycle arrest and apoptosis. A Terc−/− LSC gene expression signature predicts an improved outcome in human AML. Imetelstat prevents the expansion of human AML LSCs in patient-derived xenografts

United States Patent 8,906,615 for a method for inhibiting function of an RNA in a cell

S. Gryaznov et al. (December 9, 2014)

A method for inhibiting function of an RNA in a cell, comprising contacting the cell with a polynucleotide that can specifically hybridize with the RNA, wherein the polynucleotide comprises at least one 2'-arabino-fluoronucleoside linked to at least one additional nucleoside subunit by a linkage selected from the group consisting of N3'.fwdarw.P5' phosphoramidate and N3'.fwdarw.P5' thiophosphoramidate intersubunit linkages.

Source: USPTO

Telomerase inhibitor Imetelstat (GRN163L) limits the lifespan of human pancreatic cancer cells

K.M. Burchett et al. (2014)

GRN163L (Imetelstat) is a lipid-conjugated N3'→P5' thio-phosphoramidate oligonucleotide that blocks the template region of telomerase.../.. These findings show that the lifespan of pancreatic cancer cells can be limited by continuous telomerase inhibition. These results should facilitate the design of future clinical trials of GRN163L in patients with pancreatic cancer.

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

O.G. Gonzales et al. (2014)

The inhibition of telomerase activity by TERT- or TERC-specific RNA interference, the overexpression of dominant-negative-TERT, and the application of the telomerase inhibitor imetelstat reduce Pol I transcription and the growth of tumour cells. Our results demonstrate how non-canonical features of telomerase may direct Pol I transcription in oncogenic and regenerative hyperproliferation.

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

M. Barszczyk et al. (2014)

Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor

Y. Hu et al. (2014)

Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted. 

Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma

E. Chevret et al (2014)

Here we explored telomere length (TL) and telomerase activity (TA) in primary cutaneous T-cell lymphoma (CTCL). Telomerase inhibition rapidly impeded in vitro cell proliferation and led to cell death, while telomerase overexpression stimulated in vitro proliferation and clonogenicity properties and favored tumor development in immunodeficient mice. Our data indicate that, besides maintenance of TL, telomerase exerts additional functions in CTCL. Therefore, targeting these functions might represent an attractive therapeutic strategy, especially in aggressive CTCL. 

Use of telomerase inhibitors for the treatment of myeloproliferative disorders and myeloproliferative neoplasms  (patent publication)

M.J. Stuart, S. Kelsey (2014)

Provided herein are methods for reducing neoplastic progenitor cell proliferation and alleviating symptoms associated in individuals diagnosed with or thought to have myeloproliferative disorders, such as Essential Thrombocythemia (ET). Also provided herein are methods for using telomerase inhibitors for maintaining blood platelet counts at relatively normal ranges in the blood of individuals diagnosed with or suspected of having myeloproliferative disorders, such as ET.

Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth

R. Lu, S. Gryaznov et al (2014)

We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). Combining HR inhibition with telomerase renders telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy targeting HR and telomerase has the potential to prevent both tumor growth and genomic evolution in BAC.


Discovery of Telomeric DNA and Telomerase

E. Blackburn (2013)

Dr. Blackburn, Nobel Prize Winner for the discovery of telomerase,  explains that with each round of replication, the protective repeats, or telomeres, on the end of chromosomes shorten eventually leading to cellular senescence. Blackburn and her colleagues reasoned that there must be an enzyme that rebuilds the lost telomere so cell division can continue. She explains how this enzyme, called telomerase, was found and discusses its key role in cellular aging.

Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes

M. Shawi et al. (2013)

We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.

Imetelstat (a telomerase antagonist) exerts off‑target effects on the cytoskeleton

I. Mender et al. (2013)

Currently, GRN163L is being investigated in several clinical trials, including a phase II human non‑small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy.  ../..

These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.

Inhibitors of telomerase and of poly(ADP-Ribose)polymerases synergize to limit the lifespan of pancreatic cancer cells

K.Burchett and M.Ouellette (2013)

Telomerase is required for the unlimited lifespan of cancer cells. Pancreatic cancers are almost always positive for telomerase activity and inhibiting telomerase in these cells could limit their lifespan. In this project, we have characterized the biology of telomeres in a panel of 11 pancreatic cancer cell lines and have examined the effects of GRN163L (Imetelstat), a potent telomerase inhibitor, on these cells. GRN163L inhibited telomerase in all 11 pancreatic cancer cell lines.

2012 and before:

Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks

X. Wu et al. (2012)

Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.

Imetelstat (GRN163L): telomerase-based cancer therapy

A. Roth et al. (2010)

Telomeres and telomerase play essential roles in the regulation of the lifespan of human cells. While normal human somatic cells do not or only transiently express telomerase and therefore shorten their telomeres with each cell division, most human cancer cells typically express high levels of telomerase and show unlimited cell proliferation. Here, we report on the structure and the mechanism of action of imetelstat as well as about the preclinical and clinical data and future prospects using imetelstat in cancer therapy.

The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines

I. Joseph et al (2010)

Inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.

Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms.

S. Brennan et al (2010)

Telomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms.

Telomeres and telomerase in cancer

S.E. Artandi et al (2009)

In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.

Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer

A.E. Hochreiter et al. (2006)

The aim of this study was to address the breast cancer translational potential of the novel telomerase inhibitor, GRN163L. GRN163L effectively inhibited telomerase activity in a dose-dependent fashion in all breast cancer cell lines resulting in progressive telomere shortening. These results show in vivo effectiveness of GRN163L in breast cancer and support its promising clinical potential for breast cancer treatment.

The effects of telomerase inhibition on prostate tumor-initiating cells

C. Marian et al (2010)

Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches.Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. 

Role of telomeres and telomerase in cancer

Jerry W. Shay et al (2011)

There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. While telomerase does not drive the oncogenic process, it is permissive and required for the sustain growth of most advanced cancers. Since telomerase is not expressed in most normal human cells, this has led to the development of targeted telomerase cancer therapeutic approaches that are presently in advanced clinical trials.

The telomerase inhibitor imetelstat exhibits antitumor and anticancer stem cell effects through perturbation of casein kinase-2 signaling

Ryan T. Nitta et al (2011)

Activation of telomerase is essential for the indefinite replication potential of most cancer cells. Inhibition of telomerase is expected to lead to loss of telomere maintenance resulting in cell cycle arrest and/or cancer cell death, making telomerase inhibition an attractive anti-cancer approach.

Imetelstat, a potent telomerase inhibitor currently in Phase II clinical trials, has been shown to reduce proliferative potential in multiple cancer models. Several recent studies have demonstrated that imetelstat depletes CSCs in various tumor types.

Imetelstat inhibited telomerase activity, proliferative capacity and colony-forming potential in the U87 and U118 cell lines. Imetelstat treatment (2 weeks at 3uM) resulted in decreased expression of casein kinase 2 (CK2) subunits alpha and beta, and a reduction in phosphorylation of downstream CK2 substrates such as the DNA repair protein XRCC1. In addition, imetelstat reduced the transcriptional activity of beta-catenin, which is regulated by members of the CK2 family. 

Our results suggest that CK2-alpha signaling and dysregulation of its downstream targets may play a key role in survival of CSCs as well as bulk tumor cells in U87 and U118 glioblastoma cell lines. These novel insights may help identify drugs that can act synergistically with imetelstat in treating cancer.

Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma

Meta W. Djojosubroto et al (2005)

Most cancer cells have an immortal growth capacity as a consequence of telomerase reactivation. Inhibition of this enzyme leads to increased telomere dysfunction, which limits the proliferative capacity of tumor cells; thus, telomerase inhibition represents a potentially safe and universal target for cancer treatment.

The results suggest that telomerase inhibition could be a valid approach for HCC treatment and that GRN163L is a promising drug development candidate with significant effects on tumor growth and increased chemosensitivity to doxorubicin. Our study provides experimental evidence that telomerase inhibition by NPS oligonucleotides targeting the human telomerase RNA component template region represent a promising approach for the treatment of HCC.

The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth

C. Marian, J. Shay et al (2010)

Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.

Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45μM). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway.

This pre-clinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies.

Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma

M.W. Djojosubrotoet al (2005)

Most cancer cells have an immortal growth capacity as a consequence of telomerase reactivation. Inhibition of this enzyme leads to increased telomere dysfunction, which limits the proliferative capacity of tumor cells; thus, telomerase inhibition represents a potentially safe and universal target for cancer treatment. The studies showed that both GRN163 and GRN163L inhibited telomerase activity and tumor cell growth in a dose-dependent manner in vitro and in vivo. In conclusion, our data support the development of GRN163L, a novel lipidated conjugate of the telomerase inhibitor GRN163, for systemic treatment of human hepatoma. In addition to limiting the proliferative capacity of hepatoma, GRN163L might also increase the sensitivity of this tumor type to conventional chemotherapy.

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