title: NT113, a pan-ERBB inhibitor with high brain penetrance, inhibits the growth of glioblastoma xenografts with EGFR amplification.
abstract: This report describes results from our analysis of the activity and biodistribution of a novel pan-ERBB inhibitor, NT113, when used in treating mice with intracranial glioblastoma (GBM) xenografts. Approaches used in this investigation include: bioluminescence imaging (BLI) for monitoring intracranial tumor growth and response to therapy; determination of survival benefit from treatment; analysis of tumor IHC reactivity for indication of treatment effect on proliferation and apoptotic response; Western blot analysis for determination of effects of treatment on ERBB and ERBB signaling mediator activation; and high-performance liquid chromatography for determination of NT113 concentration in tissue extracts from animals receiving oral administration of inhibitor. Our results show that NT113 is active against GBM xenografts in which wild-type EGFR or EGFRvIII is highly expressed. In experiments including lapatinib and/or erlotinib, NT113 treatment was associated with the most substantial improvement in survival, as well as the most substantial tumor growth inhibition, as indicated by BLI and IHC results. Western blot analysis results indicated that NT113 has inhibitory activity, both in vivo and in vitro, on ERBB family member phosphorylation, as well as on the phosphorylation of downstream signaling mediator Akt. Results from the analysis of animal tissues revealed significantly higher NT113 normal brain-to-plasma and intracranial tumor-to-plasma ratios for NT113, relative to erlotinib, indicating superior NT113 partitioning to intracranial tissue compartments. These data provide a strong rationale for the clinical investigation of NT113, a novel ERBB inhibitor, in treating patients with GBM.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California. Department of Pediatrics, University of California San Francisco, San Francisco, California.
authors.forename: Tsun-Wen
authors.initials: TW
authors.lastname: Yao
authors.affiliation: NewGen Therapeutics, Inc., Menlo Park, California.
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.affiliation: NewGen Therapeutics, Inc., Menlo Park, California.
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Raizer
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Stegh
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.affiliation: Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.affiliation: Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California. Department of Pediatrics, University of California San Francisco, San Francisco, California. charles.james@northwestern.edu theodore.nicolaides@ucsf.edu.
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. charles.james@northwestern.edu theodore.nicolaides@ucsf.edu.
authors.forename: C David
authors.initials: CD
authors.lastname: James
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000600156:NT113 compound; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D000077341:Lapatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors