Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ <i>Thio</i>-Phosphoramidate Targeting Telomerase

Jackson, Shalmica R.; Zhu, Chun Hong; Paulson, Vera; Watkins, Linda R.; Dikmen, Z. Günnur; Gryaznov, Sergei M.; Wright, Woodring E.

doi:10.1158/0008-5472.can-06-2306

Cited by 69 publications

(53 citation statements)

References 31 publications

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“…35 When we attempted to achieve a more complete telomerase blockade by increasing the imetelstat concentration (8 and 16 mM), cells showed immediate toxicity, likely the result of extra-telomeric effects of imetelstat such as decreased cell adhesion and disruption of the cytoskeleton. 36,37 Such effects may be desirable for treating cancer cells, but for the purpose of the current investigation, we chose to limit the concentration of imetelstat to focus on effects related to telomere shortening.…”

Section: Discussionmentioning

confidence: 99%

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

Bobb

et al. 2015

Cancer Biology & Therapy

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, phosphorylation of H2AX, TERC, the RNA component of telomerase; TERT, the catalytic component of telomerase; TRAP, telomeric repeat amplification protocol.The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. 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. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of gH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p D 0.045, alvespimycin, p D 0.034; combined treatment, p D 0.004). 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.

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Section: Discussionmentioning

confidence: 99%

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

Bobb

et al. 2015

Cancer Biology & Therapy

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“…Our data support a role for telomerase in ependymomas in allowing proliferation as hTERT expression correlated with both increased mitotic index and MIB-1 proliferative index in our ependymoma cohort (Table 3). This is important as a variety of studies (De Semir et al, 2007;Jackson et al, 2007) have suggested other roles for telomerase in proliferating cells. Telomere maintenance in paediatric ependymomas U Tabori et al Furthermore, our data support a role for telomerase in protecting cells from DNA damage by demonstrating an inverse correlation between hTERT and gH2AX expressions (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

Tabori

Wong

et al. 2008

Br J Cancer

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We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (Po0.0001) and mitotic index (P ¼ 0.005), as well as overall tumour grade (P ¼ 0.001), but not with other markers of anaplasia. There was no correlation between telomere length and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected telomere maintenance in recurrent tumours. There was an inverse correlation between hTERT expression and telomere dysfunction as measured by gH2AX expression (P ¼ 0.016). Combining gH2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, Po0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans.

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“…GRN163L is a modified oligonucleotide complementary to hTERC and a potent and specific telomerase antagonist 66 . GRN163L effectively inhibits telomerase activity of various human cancer cell lines [67][68][69][70] , resulting in progressive telomere shortening and induction of cellular senescence to suppress tumor cell growth in vitro. Furthermore, administration of GRN163L is effective in preventing lung metastases in breast cancer xenograft animal models 68 .…”

Section: Future Anti-cancer Therapy: Therapeutic Strategies That Targmentioning

confidence: 99%

Telomere dysfunction and tumour suppression: the senescence connection

2008

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Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments. One of these anti-cancer barriers is the telomere, a specialized nucleoprotein that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.More than 40 years ago, Hayflick and Moorhead discovered that normal human diploid fibroblasts (HDFs) cannot grow indefinitely in culture 1 . Rather, their proliferative capacities are intrinsically limited. After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker 2 . We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes. Confirmation of this came from studies in which telomerase, the enzyme that maintains telomeres, was ectopically expressed in normal human somatic cells 3,4 . Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization. These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability 5 . However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation. In this Perspective, we will discuss how telomeres shorten with cell replication and how this might initiate a DNA damage response to induce replicative senescence (and cell death) and ultimately prevent tumorigenesis.

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Antiadhesive Effects of GRN163L—An Oligonucleotide N3′→P5′ Thio-Phosphoramidate Targeting Telomerase

Cited by 69 publications

References 31 publications

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

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

Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

Telomere dysfunction and tumour suppression: the senescence connection

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