title: Telomerase inhibitor imetelstat has preclinical activity across the spectrum of non-small cell lung cancer oncogenotypes in a telomere length dependent manner.
abstract: 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. A panel of 63 NSCLC cell lines was studied for telomere length and imetelstat efficacy in inhibiting colony formation and no correlation was found with patient characteristics, tumor histology, and oncogenotypes. While there was no overall correlation between imetelstat efficacy with initial telomere length (ranging from 1.5 to 20 kb), the quartile of NSCLC lines with the shortest telomeres was more sensitive than the quartile with the longest telomeres. 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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Frink
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.affiliation: Inova Schar Cancer Institute, Falls Church, VA, USA.|Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D010641:Phenotype; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D059505:Telomere Homeostasis / Q000187:drug effects*; D059506:Telomere Shortening / Q000187:drug effects*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; C519562:imetelstat
keywords: imetelstat; lung cancer; telomerase; telomerase inhibition; telomeres