Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts

Cancer Cell. 2017 Nov 13;32(5):590-607.e4. doi: 10.1016/j.ccell.2017.10.006.

Abstract

Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.

Keywords: TRF1; glioblastoma; glioma stem cells; shelterin; stemness; telomeres; therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Models, Animal*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mice, Knockout
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • RNA Interference
  • Telomere / genetics
  • Telomere / metabolism
  • Telomeric Repeat Binding Protein 1 / antagonists & inhibitors
  • Telomeric Repeat Binding Protein 1 / genetics*
  • Telomeric Repeat Binding Protein 1 / metabolism
  • Transplantation, Heterologous

Substances

  • Telomeric Repeat Binding Protein 1