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

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.
AuthorsLiMei Wang, Jennifer J Rahn, XueQing Lun, Beichen Sun, John J P Kelly, Samuel Weiss, Stephen M Robbins, Peter A Forsyth, Donna L Senger
JournalPLoS biology (PLoS Biol) Vol. 6 Issue 11 Pg. e289 (Nov 25 2008) ISSN: 1545-7885 [Electronic] United States
PMID19067488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Nerve Growth Factors
  • Receptor, Nerve Growth Factor
  • Recombinant Fusion Proteins
  • Amyloid Precursor Protein Secretases
Topics
  • Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
  • Animals
  • Brain (metabolism)
  • Brain Neoplasms (metabolism, therapy)
  • Enzyme Inhibitors (therapeutic use)
  • Glioma (metabolism, therapy)
  • Humans
  • Neoplasm Invasiveness (physiopathology)
  • Nerve Growth Factors (metabolism)
  • Receptor, Nerve Growth Factor (metabolism)
  • Recombinant Fusion Proteins

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