Radiotherapy Plus the Neurokinin-1 Receptor Antagonist Aprepitant: A Potent Therapeutic Strategy for the Treatment of Diffuse Intrinsic Pontine Glioma

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16–24 months independently of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin Neurokin-1 receptor (NK-1R) is involved in glioma progression, induces glioma cells proliferation by activating, MAPKs (p38 MAPK, ERK1/2 and JNK), c-Myc, AP-1, NF-κB, and induces antiapoptotic by PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system regulates also the migration and invasion of glioma cells, stimulates angiogenesis and triggering inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R and NK-1R is essential for the viability of glioma cells and non for normal cells. In contrast, in glioma, NK-1R antagonists, such as aprepitant drug penetrate brain and reach therapeutic concentrations: inhibit mitogenesis, induces apoptosis and inhibit breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization, radioneuroprotection, reduces both peritumoral and radiation-induced inflammation, and is also antinausea and antivomiting. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusion: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG.