Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas.
Pediatr Blood Cancer
; 63(2): 206-13, 2016 Feb.
Article
em En
| MEDLINE
| ID: mdl-26375012
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;Nf1(flox/-) pNF murine model. EXPERIMENTALDESIGN:
Proliferation, ß-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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
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Neurofibroma Plexiforme
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Microambiente Tumoral
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Indóis
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Pediatr Blood Cancer
Ano de publicação:
2016
Tipo de documento:
Article