title: A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells.
abstract: Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.
authors.affiliation: Department of Neuro-Oncology, Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Saito
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Wang
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Roel G
authors.initials: RG
authors.lastname: Verhaak
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D011480:Protease Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases
keywords: Glioma; Notch activation; Proneural genes; γ Secretase inhibitors
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