title: Validation of a preclinical model for assessment of drug efficacy in melanoma.
abstract: The aim of personalized medicine is to improve our understanding of the disease at molecular level and to optimize therapeutic management. In this context, we have developed in vivo and ex vivo preclinical strategies evaluating the efficacy of innovative drugs in melanomas. Human melanomas (n = 17) of different genotypes (mutated BRAF, NRAS, amplified cKIT and wild type) were successfully engrafted in mice then amplified by successive transplantations. The exhaustive characterization of patient-derived xenografts (PDX) at genomic level (transcriptomic and CGH arrays) revealed a similar distribution pattern of genetic abnormalities throughout the successive transplantations compared to the initial patient tumor, enabling their use for mutation-specific therapy strategies. The reproducibility of their spontaneous metastatic potential in mice was assessed in 8 models. These PDXs were used for the development of histoculture drug response assays (ex vivo) for the evaluation of innovative drug efficacy (BRAF and MEK inhibitors). The pharmacological effects of BRAF and MEK inhibitors were similar between PDX-derived histocultures and their corresponding PDX, on 2 models of BRAF and NRAS-mutated melanomas. These models constitute a validated, effective tool for preclinical investigation of new therapeutic agents, and improve therapeutic strategies in the treatment of metastatic melanoma.
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.|AP-HP, Hôpital Saint-Louis, Department of Dermatology, Paris, F-75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Delyon
authors.affiliation: INSERM UMR_S1165, Paris, F-75010, France.|Université Paris-Diderot, Department of Pathology, UMR_S1165, Paris, F-75010, France.|UMR CNRS 8612, Institut Galien-UFR de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, F-92290, France.
authors.forename: Mariana
authors.initials: M
authors.lastname: Varna
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.|INSERM UMR_1137, Paris, F-75018, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Feugeas
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Sadoux
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.
authors.forename: Saliha
authors.initials: S
authors.lastname: Yahiaoui
authors.affiliation: AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie Biologique, Paris, F-75010, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Podgorniak
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Leclert
authors.affiliation: Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.|AP-HP, Hôpital Saint-Louis, Department of Plastic, Reconstructive and Esthetic Surgery, Paris, F-75010, France.
authors.forename: Sarra Mazouz
authors.initials: SM
authors.lastname: Dorval
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.forename: Jean
authors.lastname: Soulie
authors.affiliation: INSERM UMR_S1165, Paris, F-75010, France.|Université Paris-Diderot, Department of Pathology, UMR_S1165, Paris, F-75010, France.|AP-HP, Hôpital Saint-Louis, Department of Pathology, Paris, F-75010, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.|AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie Biologique, Paris, F-75010, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.affiliation: INSERM UMR_S976, Paris, F-75010, France.|AP-HP, Hôpital Saint-Louis, Department of Dermatology, Paris, F-75010, France.|Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France.
authors.forename: Céleste
authors.initials: C
authors.lastname: Lebbé
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents
keywords: BRAF mutation; histoculture drug response assay; melanoma; model; xenograft