Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor

Cancer Genet. 2014 Sep;207(9):403-11. doi: 10.1016/j.cancergen.2014.09.002. Epub 2014 Sep 16.

Abstract

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. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. 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.

Keywords: DNA damage; GRN163L; H2AX; Telomere; atypical teratoid/rhabdoid tumor; imetelstat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromosomal Proteins, Non-Histone / biosynthesis
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Repair / drug effects*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / pharmacology
  • Female
  • Histones / biosynthesis
  • Humans
  • Indoles / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Oligonucleotides
  • Phosphorylation
  • Rhabdoid Tumor / drug therapy*
  • Rhabdoid Tumor / genetics
  • Rhabdoid Tumor / pathology
  • SMARCB1 Protein
  • Telomerase / antagonists & inhibitors*
  • Telomere Homeostasis / drug effects
  • Telomere Shortening / drug effects*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • H2AX protein, human
  • Histones
  • Indoles
  • Oligonucleotides
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Niacinamide
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Telomerase
  • imetelstat