title: Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms.
abstract: BACKGROUND
  This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Blockade of aberrant hedgehog activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally bioavailable Smoothened (Smo) antagonist LDE225 have not been examined.
  
  
  METHODS
  To assess in vivo effects, transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or LDE225 (80 mg/kg/d) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by iummohistochemsistry. Quantitative real-time polymerase chain reaction was performed for hedgehog target genes with RNA from islet, isolated from treated and untreated Rip1Tag2 mice.
  
  
  RESULTS
  LDE225 significantly reduced tumor volume by 95% compared with untreated control mice. Hedgehog inhibition with LDE225 significantly prolonged median survival in the used transgenic mouse model (105 vs 116 days; P = 0.02). Quantitative real-time polymerase chain reaction for downstream hedgehog target genes demonstrated significant downregulation in the islet cell tumors of Rip1Tag2 mice treated with LDE225, confirming the ability to achieve effective pharmacologic levels of LDE225 within the desired tissue site, in vivo.
  
  
  CONCLUSIONS
  This is the first study to show that the orally bioavailable Smo antagonist LDE225 may provide a new option for therapy of islet cell neoplasms.
authors: Department of Surgery, Philipps-University Marburg, Marburg, Germany. fendrich@med.uni-marburg.de
authors: Volker
authors: V
authors: Fendrich
authors: Dominik
authors: D
authors: Wiese
authors: Jens
authors: J
authors: Waldmann
authors: Matthias
authors: M
authors: Lauth
authors: Anna E
authors: AE
authors: Heverhagen
authors: Johannes
authors: J
authors: Rehm
authors: Detlef K
authors: DK
authors: Bartsch
mesh_terms: D007516:Adenoma, Islet Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage*; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D000072086:Smoothened Receptor
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C561435:sonidegib