title: Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts.
abstract: BACKGROUND
  Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses.
  
  
  METHODS
  We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγ(null) recipient mice, completed molecular annotation and assessed platinum sensitivity.
  
  
  RESULTS
  The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥ 100 d, n = 4), resistant (progression-free interval <100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2).
  
  
  CONCLUSIONS
  Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Monique D
authors.initials: MD
authors.lastname: Topp
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Hartley
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Michele
authors.initials: M
authors.lastname: Cook
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Royal Women's Hospital, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Valerie
authors.initials: V
authors.lastname: Heong
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Boehm
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: McShane
authors.affiliation: Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Pyman
authors.affiliation: Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Orla
authors.initials: O
authors.lastname: McNally
authors.affiliation: Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Ananda
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Marisol
authors.initials: M
authors.lastname: Harrell
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Galletta
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Alsop
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kerr
authors.affiliation: Department of Medicine and Health Sciences, Monash University, Clayton, Victoria 3168, Australia; Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Hutt
authors.affiliation: Mayo Clinic Cancer Centre, Rochester, MN, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, NSW, Australia; Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.lastname: Australian Ovarian Cancer Study
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 8006, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 8006, Australia.
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Genetics, University of Melbourne, Melbourne, Victoria 8006, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wakefield
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Royal Women's Hospital, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address: scottc@wehi.edu.au.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D002945:Cisplatin / Q000627:therapeutic use*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D002945:Cisplatin
keywords: BRCA1; BRCA2; DNA repair; Platinum; Serous ovarian cancer; Xenograft