Validation of a preclinical model for assessment of drug efficacy in melanoma

// Julie Delyon 1,2,3 , Mariana Varna 4,5,6 , Jean-Paul Feugeas 3,7 , Aurélie Sadoux 1 , Saliha Yahiaoui 1 , Marie-Pierre Podgorniak 8 , Geoffroy Leclert 1 , Sarra Mazouz Dorval 3,9 , Nicolas Dumaz 1,3 , Anne Janin 4,5,10 , Samia Mourah 1,3,8,* and Céleste Lebbé 1,2,3,* 1 INSERM UMR_S976, Paris, F-75010, France 2 AP-HP, Hôpital Saint-Louis, Department of Dermatology, Paris, F-75010, France 3 Université Paris-Diderot, Sorbonne Paris Cité, Paris, F-75013, France 4 INSERM UMR_S1165, Paris, F-75010, France 5 Université Paris-Diderot, Department of Pathology, UMR_S1165, Paris, F-75010, France 6 UMR CNRS 8612, Institut Galien-UFR de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, F-92290, France 7 INSERM UMR_1137, Paris, France 8 AP-HP, Hôpital Saint-Louis, Laboratoire de Pharmacologie Biologique, Paris, F-75010, France 9 AP-HP, Hôpital Saint-Louis, Department of Plastic, Reconstructive and Esthetic Surgery, Paris, F-75010, France 10 AP-HP, Hôpital Saint-Louis, Department of Pathology, Paris, F-75010, France * These authors have contributed equally to this work Correspondence to: Julie Delyon, email: // Keywords : histoculture drug response assay, xenograft, BRAF mutation, melanoma, model Received : September 07, 2015 Accepted : January 18, 2016 Published : February 20, 2016 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.