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

Authors

LiMei Wang, Jennifer J Rahn, XueQing Lun, Beichen Sun, John J. P Kelly, Samuel Weiss, Stephen M Robbins, Peter A Forsyth, and Donna L Senger

Details

Published in PLoS Biology. 2008 Nov; 6(11): e289.,
Published online 2008 Nov 25. doi: 10.1371/journal.pbio.0060289
Read the full article at PLoS Biology or at NIH PMC

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.

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