title: Inhibition of the NOTCH pathway using γ-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors.
abstract: Notch signaling is altered in many cancers. Our previous findings in primary pediatric ependymoma support a role for NOTCH in glial oncogenesis. The present study evaluates the γ-secretase inhibitor RO4929097 in glial tumor models. The expression of Notch pathway genes was evaluated using real-time RT-PCR in 21 ependymoma and glioma models. NOTCH1 mutations were analyzed by DNA sequencing. RO4929097 activity was evaluated in vitro and in vivo, as a single agent and in combination, in glioma and ependymoma models. Notch pathway genes are overexpressed in ependymomas and gliomas along with FBXW7 downregulation. NOTCH1 mutations in the TAD domain were observed in 20% (2/10) of ependymoma primary cultures. Blocking the Notch pathway with the γ-secretase inhibitor RO4929097 reduced cell density and viability in ependymoma short-term cultures. When combined with chemotherapeutic agents, RO4929097 enhanced temozolomide effects in ependymoma short-term cultures and potentiated the cytotoxicity of etoposide, cisplatinum, and temozolomide in glioma cells. RO4929097, in combined treatment with mTOR inhibition, potentiated cytotoxicity in vitro, but did not enhance antitumor effects in vivo. In contrast, RO4929097 enhanced irradiation effects in glioma and ependymoma xenografts and showed tumor growth inhibition in advanced-stage IGRG121 glioblastoma xenografts. RO4929097-mediated effects were independent of NOTCH1 mutation status or expression levels, but associated with low IL-6 levels. In established glial tumor models, NOTCH inhibition had limited effects as a single agent, but enhanced efficacy when combined with DNA-interfering agents. These preclinical data need to be considered for further clinical development of NOTCH inhibitors in glial tumors.
authors.affiliation: aGustave Roussy, Vectorology and Anticancer Therapeutics, Villejuif bUniversité Paris-Sud cCentre National de Recherche Scientifique (CNRS), Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France dDepartment of Neurosurgery, Necker Enfants-Malades Hospital, Paris-Descartes University, Paris ePediatric American Memorial Hospital, CHU Reims, Reims, France fHoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Carmela
authors.initials: C
authors.lastname: Dantas-Barbosa
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bergthold
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos-Dubus
authors.forename: Heike
authors.initials: H
authors.lastname: Blockus
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
authors.forename: Celine
authors.initials: C
authors.lastname: Ferreira
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puget
authors.forename: Michel
authors.initials: M
authors.lastname: Abely
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004806:Ependymoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C497761:NOTCH1 protein, human; C401859:temsirolimus; C546842:MTOR protein, human; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons