Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

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Abstract
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 γ-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 γ-secretase inhibitors may have direct clinical application for the treatment of malignant glioma. Despite technical advances, clinical prognosis of patients with malignant glioma, with an average survival of less than one year, has not changed. The highly invasive nature of these tumors, together with the recently identified brain tumor-initiating cells, provide disease reservoirs that render these tumors incurable by conventional therapies. Here, we present the first evidence to our knowledge that regulated intramembrane proteolysis of the neurotrophin receptor p75NTR is a critical regulator of glioma invasion. Inhibition of this process by clinically relevant γ-secretase inhibitors dramatically impairs the highly invasive nature of genetically distinct glioblastomas and brain tumor-initiating cells and prolongs survival. These data highlight regulated intramembrane proteolysis as a therapeutic target of malignant glioma and implicate the application of γ-secretase inhibitors in the treatment of these devastating tumors.

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