%0 Journal Article
%T Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
%A LiMei Wang
%A Jennifer J Rahn
%A XueQing Lun
%A Beichen Sun
%A John J. P Kelly
%A Samuel Weiss
%A Stephen M Robbins
%A Peter A Forsyth equal contributor
%A Donna L Senger equal contributor
%J PLOS Biology
%D 2008
%I Public Library of Science (PLoS)
%R 10.1371/journal.pbio.0060289
%X The multifunctional signaling protein p75 neurotrophin receptor (p75NTR) 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 p75NTR is required for p75NTR-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75NTR or treatment of animals bearing p75NTR-positive intracranial tumors with clinically applicable ¦Ã-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75NTR was observed in p75NTR-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75NTR as a therapeutic target, suggesting that ¦Ã-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.
%U http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060289