title: Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2.
abstract: OBJECTIVE
  The growth and survival of neurofibromatosis type 2 (NF2)-deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.
  
  
  METHODS
  We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.
  
  
  RESULTS
  NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis.
  
  
  CONCLUSIONS
  HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies.
authors.affiliation: Center for Neural Tumor Research and Section on Genetics of Hereditary Ear Disorders, House Research Institute, University of California, Los Angeles, CA 90057, USA.
authors.forename: Karo
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chareyre
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Jessen
authors.forename: Jan
authors.initials: J
authors.lastname: Manent
authors.forename: Michiko
authors.initials: M
authors.lastname: Niwa-Kawakita
authors.forename: Ruihong
authors.initials: R
authors.lastname: Chen
authors.forename: Cory H
authors.initials: CH
authors.lastname: White
authors.forename: Jeremie
authors.initials: J
authors.lastname: Vitte
authors.forename: Zahara M
authors.initials: ZM
authors.lastname: Jaffer
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rubenstein
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D016518:Neurofibromatosis 2 / Q000188:drug therapy* / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D059748:Proteolysis; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C112969:HSP90AA1 protein, human; C493165:HSP90AB1 protein, human; D007783:Lactones; D010091:Oximes; C555907:pochoxime A