A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer

Chiappori, Alberto; Kolevska, Tatjana; Spigel, David R.; Hager, Steven; Rarick, Mark U.; Gadgeel, Shirish M.; Blais, Normand; Pawel, Joachim von; Hart, Lowell L.; Reck, Martin; Bassett, Ekaterina; Burington, Bart; Schiller, Joan H.

doi:10.1093/annonc/mdu550

Cited by 141 publications

(130 citation statements)

References 19 publications

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“…For the role of imetelstat (a telomerase inhibitor) in maintenance therapy has not been well established [20], a sensitivity analysis recalculating the pooled HRs after excluding this trial and those trials at high risk of bias was therefore performed. The probability of publication bias was assessed using funnel plots and Egger test [21].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis

Zhou

Jiang

et al. 2015

Lung Cancer

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Section: Resultsmentioning

confidence: 99%

“…1, 13 trials met the inclusion criteria and were eligible for the meta-analysis [4][5][6][7][8]13,14,20,[22][23][24][25][26], with a total of 4960 patients. Overall, twelve trials were fully published journal articles [4][5][6][7][8]13,14,20,[22][23][24][25], while one was published as meeting abstract [26].…”

Section: Characteristics Of the Trialsmentioning

confidence: 99%

The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis

Zhou

Jiang

et al. 2015

Lung Cancer

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“…19,20 Less promising results were observed with solid tumors, including breast cancer and non-small cell lung cancer. 21,22 However, a recent Children's Oncology Group phase 1 study of imetelstat for children with recurrent solid tumors observed partial responses in one patient with Ewing sarcoma and one patient with osteosarcoma. 23 Our results indicate that combination therapy may enhance the effect of imetelstat as a single agent.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18] Phase 1 and 2 clinical trials demonstrated a favorable pharmacokinetic and side effect profile for imetelstat, though with mixed clinical results. 14,[19][20][21][22][23] Although telomerase activity is regulated largely at the level of transcription of TERT, the gene that encodes the catalytic component of the telomerase enzyme complex, it has become clear that telomerase regulation is complex and also involves posttranslational modifications, alternative splicing, and binding to chaperone proteins. 24,25 HSP90 plays a key role in the folding and function of TERT and more than 200 other oncogenic proteins including C-RAF, CDK4, AKT/PKB, mutant p53, and HIF-1a.…”

Section: Introductionmentioning

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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“…[3][4][5][6][7][8] However, clinical trials in breast, lung, and pediatric brain cancer were halted due to hematopoietic toxicity that may have resulted from nonselective hTERT inhibition in stem cells. [9][10][11] Trials are now ongoing in myeloproliferative disease with promising results in myelofibrosis and essential thrombocythemia. 12,13 hTERT is the catalytic subunit of the telomerase holoenzyme.…”

Section: Introductionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer

Cited by 141 publications

References 19 publications

The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis

The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis

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

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

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