title: Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial.
abstract: OBJECTIVE
  High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role.
  
  
  METHODS
  In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment.
  
  
  RESULTS
  Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors.
  
  
  CONCLUSIONS
  The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786-96. ©2016 AACR.
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Shimizu
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Koos
authors.initials: K
authors.lastname: Hovinga
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sasan
authors.initials: S
authors.lastname: Karimi
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leif
authors.initials: L
authors.lastname: Droms
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kyung K
authors.initials: KK
authors.lastname: Peck
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Philip
authors.initials: P
authors.lastname: Gutin
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: J Bryan
authors.initials: JB
authors.lastname: Iorgulescu
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaley
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lisa
authors.initials: L
authors.lastname: DeAngelis
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Pentsova
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Craig
authors.initials: C
authors.lastname: Nolan
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christian
authors.initials: C
authors.lastname: Grommes
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Timothy
authors.initials: T
authors.lastname: Chan
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dylan
authors.initials: D
authors.lastname: Bobrow
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Adilia
authors.initials: A
authors.lastname: Hormigo
authors.affiliation: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Analytical Pharmacology Core, Memorial Sloan Kettering Cancer Center, New York, New York. LipoSeuticals Inc, Princeton, New Jersey.
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.affiliation: Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.affiliation: Epidemiology and Statistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katherine
authors.initials: K
authors.lastname: Panageas
authors.affiliation: National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, Maryland.
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York. tabarv@mskcc.org.
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
mesh_terms: D000328:Adult; D000368:Aged; D001552:Benzazepines / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D059248:Chemoradiotherapy / Q000379:methods; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D005466:Fluorocarbons
chemical_list: D001552:Benzazepines; D051880:Receptors, Notch; 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