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Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas
Author(s) -
Ferguson Michael J.,
Rhodes Steven D.,
Jiang Li,
Li Xiaohong,
Yuan Jin,
Yang Xianlin,
Zhang Shaobo,
Vakili Saeed T.,
Territo Paul,
Hutchins Gary,
Yang FengChun,
Ingram David A.,
Clapp D. Wade,
Chen Shi
Publication year - 2016
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.25763
Subject(s) - sunitinib , sunitinib malate , medicine , cancer research , neurofibromatosis , pharmacology , pathology , renal cell carcinoma
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;Nf1 flox/− 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;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. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.