title: Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected patients to variable numbers of benign neurofibromas. To date there are no effective chemotherapeutic drugs available for this slow growing tumor. Molecularly targeted agents that aim to slow neurofibroma growth are being tested in clinical trials. So preclinical models for testing potential therapies are urgently needed to prioritize drugs for clinical trials of neurofibromas.
  
  
  METHODS
  We used magnetic resonance imaging (MRI) to monitor neurofibroma development in the Nf1(flox/flox) ;DhhCre mouse model of GEM grade I neurofibroma. Based on studies implicating mTOR and Raf signaling in NF1 mutant cells, we tested the therapeutic effect of RAD001 and Sorafenib in this model. Mice were scanned to establish growth rate followed by 8 weeks of drug treatment, then re-imaged after the last dose of drug treatment. Tumor volumes were determined by volumetric measurement.
  
  
  RESULTS
  We found that rate of tumor growth varied among mice, as it does in human patients. RAD001 inhibited its predicted target pS6K, yet there was no significant decrease in the tumor volume in RAD001 treated mice compared to the vehicle control group. Sorafenib inhibited cyclinD1 expression and cell proliferation in tumors, and volumetric measurements identified significant decreases in tumor volume in some mice.
  
  
  CONCLUSIONS
  The data demonstrate that volumetric MRI analysis can be used to monitor the therapeutic effect in the preclinical neurofibroma drug screening, and suggest that Sorafenib might have clinical activity in some neurofibromas.
authors.affiliation: Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.forename: R
authors.initials: R
authors.lastname: Scott Dunn
authors.forename: Diana
authors.initials: D
authors.lastname: Lindquist
authors.forename: Beverly M
authors.initials: BM
authors.lastname: Schnell
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Aerang
authors.initials: A
authors.lastname: Kim
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D000068338:Everolimus; D005260:Female; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D019426:Integrases / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000473:pathology*; D025542:Neurofibromin 1 / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077157:Sorafenib; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D053823:Hedgehog Proteins; D007166:Immunosuppressive Agents; D025542:Neurofibromin 1; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; C045073:Cre recombinase; D019426:Integrases; D020123:Sirolimus