title: Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.
abstract: NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation.
authors.affiliation: From the Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center (ICT, MH-C, WB, CGE, EHR) and Division of Pediatric Oncology (ICT, EHR), Johns Hopkins University, Bloomberg Children's Hospital, Baltimore, Maryland; Children's National Medical Center and George Washington University School of Medicine and Health Sciences, Washington, District of Columbia (MK, JN); Department of Neurology and Ophthalmology, Michigan State University, East Lansing (HTC); and Sparrow Health System, Lansing (HTC), Michigan; and Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (KEW).
authors.forename: Isabella C
authors.initials: IC
authors.lastname: Taylor
authors.forename: Marianne
authors.initials: M
authors.lastname: Hütt-Cabezas
authors.forename: William D
authors.initials: WD
authors.lastname: Brandt
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kambhampati
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
authors.forename: Howard T
authors.initials: HT
authors.lastname: Chang
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Warren
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Eric H
authors.initials: EH
authors.lastname: Raabe
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D020295:Brain Stem Neoplasms / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011149:Pons / Q000378:metabolism / Q000473:pathology*; D011836:Radiation Tolerance / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins