Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.

摘要: NOTCH regulates stem cells during normal development and stemlike in cancer, but the roles of lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express cell factors such as SOX2 MYCN, we hypothesized that activity would be critical for DIPG growth. We determined primary expressed high levels receptors, ligands, downstream effectors. Treatment lines JHH-DIPG1 SF7761 with γ-secretase inhibitor MRK003 suppressed level effectors HES1, HES4, HES5; inhibited growth by 75%; caused a 3-fold induction apoptosis. Short hairpin RNAs targeting canonical pathway similar effects. Pretreatment clonogenic more than 90% enhanced efficacy radiation therapy. The MYCN led us to test sequential therapy bromodomain JQ1 MRK003, found induced Together, these results suggest dual may an effective therapeutic strategy adding efficacious initially or reirradiation.