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- W2079480908 abstract "Melanomas account for a notable proportion of cancers worldwide. The heterogeneity and biological characteristics of melanomas present unique therapeutic challenges. Recently a number of somatic mutations were determined, which influence the prognosis and thus therapeutic needs markedly. Here we present a panel of patient-derived melanoma xenografts, established by Oncotest from primary patient material. From 80 patient explants, growth in serial passage was observed in 43% of the cases. Molecular profiling included mutational analysis for BRAF, PI3Kalpha, KRAS, NRAS, TP53, CTNNB1, MET and JAK3 using OncoCarta ™ and exon sequencing. The chemosensitivity profile was determined in vitro using 2D and 3D culture assays. Clinically relevant BRAF mutations were the most prevalent mutation and were found in almost two thirds of the melanoma models. The second most common gene mutated was NRAS, with about one quarter of the models harbouring activating mutations of NRAS. PI3Kalpha mutations were rare, and for KRAS no mutations were detected. Most of the melanomas showed multiple mutations of the investigated genes. Chemosensitivity profiling included cytotoxic (e.g. cisplatin, carboplatin, vinblastine, vincristine, ifosfamide, paclitaxel, and docetaxel), as well as targeted drugs (e.g. sorafenib and PLX-4720). The compounds showed diverse patterns of selectivity and potency: Differential activity was determined e.g. for vinblastine, vincristine, paclitaxel, and docetaxel, but also for the BRAF inhibitor PLX-4720. PLX-4720 was most active in melanoma models carrying the BRAF mutation as determined in monolayer and soft agar assays. Activity of vincristine revealed a correlation of sensitivity with a BRAF wild type genotype and resistance with BRAF mutation. The latter result was also described recently for melanoma patients with BRAF mutations, showing a diminished duration of response to treatment with vincristine, dacarbazine, bleomycin, lomustine, and human leukocyte interferon. A collection of 25 patient-derived melanoma models is presented. Their mutational status as well as their responsiveness towards many cytotoxic and targeted agents was analyzed. This extensive genotypic and phenotypic characterization makes them a valuable tool for hypothesis generation and testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C110." @default.
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- W2079480908 date "2011-11-12" @default.
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- W2079480908 title "Abstract C110: Mutation and chemosensitivity profile of a panel of 25 patient-derived melanoma xenografts." @default.
- W2079480908 doi "https://doi.org/10.1158/1535-7163.targ-11-c110" @default.
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