title: Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.
abstract: Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.
  
  
  CONCLUSIONS
  Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Maria Romina
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Gremel
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lee
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Rothwell
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Mandal
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Kok Haw Jonathan
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Grazia
authors.initials: G
authors.lastname: Saturno
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Franziska
authors.initials: F
authors.lastname: Baenke
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Rogan
authors.affiliation: Research Services, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Swan
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.affiliation: The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.affiliation: The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Deemesh
authors.initials: D
authors.lastname: Oudit
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhomen
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Ged
authors.initials: G
authors.lastname: Brady
authors.affiliation: The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, United Kingdom. richard.marais@cruk.manchester.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D001706:Biopsy; D016000:Cluster Analysis; D019468:Disease Management; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008545:Melanoma / Q000175:diagnosis* / Q000188:drug therapy*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D057285:Precision Medicine; D015203:Reproducibility of Results; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor