Use of xenografts for preclinical drug testing

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Abstract

Uveal melanoma(UM) originates from melanocytes just like cutaneous melanoma (CM) and similar to CM, the MAPK pathway is involved in the development of UM. However, in vitro we showed an inverse correlation between MAPK and c-Met activation with increasing metastatic potential of UM. In this study, we aimed to target both Src and c-Met with repectively Dasatinib and Crizotinib in an experimental xenograft model. We used tissue derived from three different human primary tumours which were subcutaneously transplanted in mice. We used the c-Met inhibitor Crizotinib to inhibit c-Met function and Dasatinib to inhibit MAPK via Src. We monitored pharmacodynamics and analysed treatment efficacy with kinase assays. Growth inhibition was seen after treatment with Dasatinib in all three tumours. Crizotinib treatment had no marked effect on tumour size but showed, like Dasatinib, substantial effects on kinase activity. Src and c-Met show susceptibility towards their inhibitors in vivo. Dasatinib showed an effect on both tumour growth and MAPK activity where Crizotinib effects remained limited to c-Met inhibition. Combined, these results support our in vitro pathway analysis and warrants for clinical trials with these compounds in UM.

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