Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor.
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.
Wang
LiMei
L
Department of Oncology, University of Calgary, and Tom Baker Cancer Centre, Calgary, Canada.
Rahn
Jennifer J
JJ
Lun
XueQing
X
Sun
Beichen
B
Kelly
John J P
JJ
Weiss
Samuel
S
Robbins
Stephen M
SM
Forsyth
Peter A
PA
Senger
Donna L
DL
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005910:Glioma / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins
D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D020800:Receptor, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases