title: Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas.
abstract: OBJECTIVE
  Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3-kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood-brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42.
  
  
  METHODS
  In vivo mouse studies.
  
  
  METHODS
  AR42 was dosed orally in murine schwannoma allografts and human VS xenografts. Magnetic resonance imaging was used to quantify changes in tumor volume, and intracellular molecular targets were analyzed using immunohistochemistry. BBB penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate toxicity.
  
  
  RESULTS
  Growth of schwannoma implants was dramatically decreased by AR42 at doses correlating with AKT dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the BBB, and wild-type mice fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities.
  
  
  CONCLUSIONS
  AR42 suppresses schwannoma growth at doses correlating with AKT pathway inhibition. This orally bioavailable drug penetrates the BBB, is well tolerated, and represents a novel candidate for translation to human VS clinical trials.
authors: Department of Surgery, Division of Otolaryngology, University of Arizona, Tucson, Arizona 85724, USA. ajacob@surgery.arizona.edu
authors: Abraham
authors: A
authors: Jacob
authors: Janet
authors: J
authors: Oblinger
authors: Matthew L
authors: ML
authors: Bush
authors: Victoria
authors: V
authors: Brendel
authors: Griffin
authors: G
authors: Santarelli
authors: Abhik R
authors: AR
authors: Chaudhury
authors: Samuel
authors: S
authors: Kulp
authors: Krista M D
authors: KM
authors: La Perle
authors: Ching-Shih
authors: CS
authors: Chen
authors: Long-Sheng
authors: LS
authors: Chang
authors: D Bradley
authors: DB
authors: Welling
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009464:Neuroma, Acoustic / Q000188:drug therapy*; D010654:Phenylbutyrates / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates