Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas

Michael J. Ferguson, Steven D. Rhodes, Li Jiang, Xiaohong Li, Jin Yuan, Xianlin Yang, Shaobo Zhang, Saeed T. Vakili, Paul Territo, Gary Hutchins, Feng-Chun Yang, David A. Ingram, D. Wade Clapp, Shi Chen

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Purpose: 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;Nf1flox/− pNF murine model. Experimental Design: Proliferation, β-hexosaminidase release (degranulation), and Erk1/2 phosphorylation were assessed in sunitinib treated Nf1+/− mast cells and fibroblasts, respectively. Krox20;Nf1flox/- mice with established pNF were treated sunitinib or PBS-vehicle control for a duration of 12 weeks. pNF metabolic activity was monitored by serial [18F]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;Nf1flox/− 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;Nf1flox/− mice. These preclinical findings demonstrate the utility of inhibiting multiple RTKs in pNF and provide insights into the design of future clinical trials. Pediatr Blood Cancer

Original languageEnglish (US)
Pages (from-to)206-213
Number of pages8
JournalPediatric Blood and Cancer
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

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Keywords

  • neurofibromatosis type 1
  • plexiform neurofibroma
  • preclinical mouse model
  • receptor tyrosine kinase
  • sunitinib malate
  • therapy

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Medicine(all)
  • Hematology
  • Oncology

Cite this

Ferguson, M. J., Rhodes, S. D., Jiang, L., Li, X., Yuan, J., Yang, X., Zhang, S., Vakili, S. T., Territo, P., Hutchins, G., Yang, F-C., Ingram, D. A., Clapp, D. W., & Chen, S. (2016). Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatric Blood and Cancer, 63(2), 206-213. https://doi.org/10.1002/pbc.25763