title: Patient-derived tumor xenograft model to guide the use of BRAF inhibitors in metastatic melanoma.
abstract: Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([(18)F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [(18)F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.
authors.affiliation: Inserm Unit 837 Team 4, University of Medicine, Lille,  Cedex, France. pierre.guerreschi@chru-lille.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Guerreschi
authors.forename: Camille
authors.initials: C
authors.lastname: Scalbert
authors.forename: Ahmad
authors.initials: A
authors.lastname: Qassemyar
authors.forename: Jerome
authors.initials: J
authors.lastname: Kluza
authors.forename: Laura
authors.initials: L
authors.lastname: Ravasi
authors.forename: Damien
authors.initials: D
authors.lastname: Huglo
authors.forename: Veronique
authors.initials: V
authors.lastname: Martinot-Duquennoy
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D016513:Mice, SCID; D064847:Multimodal Imaging; D009154:Mutation; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019275:Radiopharmaceuticals; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden / Q000187:drug effects; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D019788:Fluorodeoxyglucose F18; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf