title: Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas.
abstract: OBJECTIVE
  Plexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Disruption of aberrant SCF/c-Kit signaling emanating from the pNF microenvironment induced the first ever objective therapeutic responses in a recent phase 2 trial. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c-Kit, PDGFR, and VEGFR, which have also been implicated in the pathogenesis of these lesions. Here, we evaluate the efficacy of sunitinib malate in a preclinical Krox20;Nf1(flox/-) pNF murine model.
  
  
  METHODS
  Proliferation, β-hexosaminidase release (degranulation), and Erk1/2 phosphorylation were assessed in sunitinib treated Nf1(+/-) mast cells and fibroblasts, respectively. Krox20;Nf1(flox/-) mice with established pNF were treated sunitinib or PBS-vehicle control for a duration of 12 weeks. pNF metabolic activity was monitored by serial [(18)F]DG-PET/CT imaging.
  
  
  RESULTS
  Sunitinib suppressed multiple in vitro gain-in-functions of Nf1(+/-) mast cells and fibroblasts and attenuated Erk1/2 phosphorylation. Sunitinib treated Krox20;Nf1(flox/-) mice exhibited significant reductions in pNF size, tumor number, and FDG uptake compared to control mice. Histopathology revealed reduced tumor cellularity and infiltrating mast cells, markedly diminished collagen deposition, and increased cellular apoptosis in sunitinib treated pNF.
  
  
  CONCLUSIONS
  Collectively, these results demonstrate the efficacy of sunitinib in reducing tumor burden in Krox20;Nf1(flox/-) mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ferguson
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Saeed T
authors.initials: ST
authors.lastname: Vakili
authors.affiliation: Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Paul
authors.initials: P
authors.lastname: Territo
authors.affiliation: Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Gary
authors.initials: G
authors.lastname: Hutchins
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.|Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.|Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.|Herman B Wells Center for Pediatric Research, Indianapolis, Indiana.
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018318:Neurofibroma, Plexiform / Q000473:pathology*; D049268:Positron-Emission Tomography; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: neurofibromatosis type 1; plexiform neurofibroma; preclinical mouse model; receptor tyrosine kinase; sunitinib malate; therapy