Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor

PLoS Biol. 2008 Nov 25;6(11):e289. doi: 10.1371/journal.pbio.0060289.

Abstract

The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Brain / metabolism
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / therapy
  • Enzyme Inhibitors / therapeutic use*
  • Glioma / metabolism*
  • Glioma / therapy
  • Humans
  • Neoplasm Invasiveness / physiopathology
  • Nerve Growth Factors / metabolism
  • Receptor, Nerve Growth Factor / metabolism*
  • Recombinant Fusion Proteins

Substances

  • Enzyme Inhibitors
  • Nerve Growth Factors
  • Receptor, Nerve Growth Factor
  • Recombinant Fusion Proteins
  • Amyloid Precursor Protein Secretases