title: Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model.
  
  
  METHODS
  We studied effects of MEK inhibition using 1.5 mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 (flox/flox); Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5 mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints.
  
  
  RESULTS
  Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage.
  
  
  CONCLUSIONS
  Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Tilat A
authors.initials: TA
authors.lastname: Rizvi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Janhofer
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.affiliation: Division of Imaging Resource Center, Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Dunn
authors.affiliation: Department of Pediatrics, Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Masters
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009456:Neurofibromatosis 1 / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D020930:MAP Kinase Kinase Kinases
keywords: MEK; NF1; nerve; neurofibroma; therapy