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

ABSTRACT: Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'?P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. 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. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. 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.

SUBMITTER: Mender I

PROVIDER: S-EPMC4738197 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Mender Ilgen I Senturk Serif S Ozgunes Nuriman N Akcali K Can KC Kletsas Dimitris D Gryaznov Sergei S Can Alp A Shay Jerry W JW Dikmen Z Gunnur ZG

International journal of oncology 20130327 5

Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials ...[more]

PMID: 23545855

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Project description:BACKGROUND:Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS:The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS:Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS:Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

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

Publications

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

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