Testing ATRA and MEK inhibitor PD0325901 effectiveness in a nude mouse model for human MPNST xenografts

Abstract Objective Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas characterized by high recurrence rates and early metastases. These tumors arise more frequently within neurofibromatosis type 1 (NF1) and present with resistance during standard chemotherapy leading to increased mortality and morbidity in those patients. In vitro all-trans retinoic acid (ATRA) and MEK inhibitors (MEKi) were shown to inhibit tumor proliferation, especially when applied in combination. Therefore, we established a nude mouse model to investigate if treatment of xenografts derived from NF1 associated S462 and T265 MPNST cells respond to ATRA and the MEKi PD0325901. Results We demonstrated that human NF1 associated MPNST derived from S462 but not T265 cells form solid subcutaneous tumors in Foxn1 nude mice but not in Balb/c, SHO or Shorn mice. We verified a characteristic staining pattern of human MPNST xenografts by immunohistochemistry. Therapeutic effects of ATRA and/or MEKi PD0325901 on growth of S462 MPNST xenografts in Foxn1 nude mice were not demonstrated in vitro, as we did not observe significant suppression of MPNST growth compared with placebo treatment

In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1–3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration

MOESM1 of Testing ATRA and MEK inhibitor PD0325901 effectiveness in a nude mouse model for human MPNST xenografts

Additional file 1. Mean tumor volumes. Description of data: Mean volumes of transplanted MPNST (mmÂł) of two treatment groups (mice treated with ATRA and with MEKi) and of placebo group. Tumors were measured from day 7 until day 68 post transplantation. Treatment started at day 42. Average volumes and standard deviation over the whole group per day as well as difference of volumes between day 42 and 68 are given

Núcleos de Ensino da Unesp: artigos 2013: volume 2: metodologias de ensino e a apropriação de conhecimento pelos alunos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Núcleos de Ensino da Unesp: artigos 2013: volume 2: metodologias de ensino e a apropriação de conhecimento pelos alunos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP