A High Notch Pathway Activation Predicts Response to γ Secretase Inhibitors in Proneural Subtype of Glioma Tumor-Initiating Cells

摘要: Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, response to therapy. However, a number small molecule inhibitors under development vary strength subset pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling is an evolutionarily conserved plays important role multiple cellular developmental processes. We investigated the effects inhibition glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing 16 GICs showed differential growth responses inhibitors, stratifying into responders nonresponders. Responder had enriched proneural gene signature comparison Also set enrichment analysis revealed 17 genes representing active components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, so on, responder group. Analysis Cancer Genome Atlas expression dataset identified group (43.9%) showing high activation suggesting might be potential value treat particular glioblastoma (GBM). Inhibition by inhibitor treatment attenuated proliferation self-renewal induces both neuronal astrocytic differentiation. In vivo evaluation demonstrated prolongation median survival intracranial mouse model. Our results suggest GBM characterized may exhibit greater sensitivity treatment, holding promise improve efficiency current