title: Chemotherapy-induced dynamic gene expression changes in vivo are prognostic in ovarian cancer.
abstract: BACKGROUND
  The response of ovarian cancer patients to carboplatin and paclitaxel is variable, necessitating identification of biomarkers that can reliably predict drug sensitivity and resistance. In this study, we sought to identify dynamically controlled genes and pathways associated with drug response and its time dependence.
  
  
  METHODS
  Gene expression was assessed for 14 days post-treatment with carboplatin or carboplatin-paclitaxel in xenografts from two ovarian cancer models: platinum-sensitive serous adenocarcinoma-derived OV1002 and a mixed clear cell/endometrioid carcinoma-derived HOX424 with reduced sensitivity to platinum.
  
  
  RESULTS
  Tumour volume reduction was observed in both xenografts, but more dominantly in OV1002. Upregulated genes in OV1002 were involved in DNA repair, cell cycle and apoptosis, whereas downregulated genes were involved in oxygen-consuming metabolic processes and apoptosis control. Carboplatin-paclitaxel triggered a more comprehensive response than carboplatin only in both xenografts. In HOX424, apoptosis and cell cycle were upregulated, whereas Wnt signalling was inhibited. Genes downregulated after day 7 from both xenografts were predictive of overall survival. Overrepresented pathways were also predictive of outcome.
  
  
  CONCLUSIONS
  Late expressed genes are prognostic in ovarian tumours in a dynamic manner. This longitudinal gene expression study further elucidates chemotherapy response in two models, stressing the importance of delayed biomarker detection and guiding optimal timing of biopsies.
authors.affiliation: School of Biology, Sir Harold Mitchell Building, University of St Andrews, St Andrews, Fife KY16 9TH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Koussounadis
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Langdon
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, Fife KY16 9TF, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: School of Biology, Sir Harold Mitchell Building, University of St Andrews, St Andrews, Fife KY16 9TH, UK.
authors.forename: V A
authors.initials: VA
authors.lastname: Smith
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D016190:Carboplatin / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D017239:Paclitaxel / Q000494:pharmacology*; D011379:Prognosis; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016190:Carboplatin; D017239:Paclitaxel