Reference Detail

Ref Type Journal Article
PMID (26115193)
Authors Taylor IC, Hütt-Cabezas M, Brandt WD, Kambhampati M, Nazarian J, Chang HT, Warren KE, Eberhart CG, Raabe EH
Title Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition.
Journal Journal of neuropathology and experimental neurology
Vol 74
Issue 8
Date 2015 Aug
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown brain stem glioma not applicable MRK-003 Preclinical - Cell culture Actionable In a preclinical study, MRK-003 increased apoptosis and decreased growth of diffuse pontine glioma cell lines in culture (PMID: 26115193). 26115193
Unknown unknown brain stem glioma not applicable JQ1 + MRK-003 Preclinical - Cell culture Actionable In a preclinical study, the combination of MRK-003 and JQ1 resulted in increased apoptosis of diffuse pontine glioma cell lines in culture, compared to either agent alone (PMID: 26115193). 26115193
Unknown unknown brain stem glioma not applicable MRK-003 + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, MRK-003 enhanced sensitivity of diffuse pontine glioma cell lines to radiotherapy in culture, resulting in increased apoptosis (PMID: 26115193). 26115193