title: Toward operative in vivo fluorescence imaging of the c-Met proto-oncogene for personalization of therapy in ovarian cancer.
abstract: BACKGROUND
  Standard biomarker testing of a single macroscopic disease site is unlikely to be sufficient because of tumor heterogeneity. A focus on examining global biomarker expression or activity, particularly in microscopic residual chemotherapy-resistant disease, is needed for the appropriate selection of targeted therapies. This study was aimed at establishing a technique for the assessment of biomarkers of ovarian cancer peritoneal spread.
  
  
  METHODS
  An in-house developed fluorescent imaging device was used to detect the expression of the c-Met oncogene in ovarian cancer. A modified cyanine 5-tagged peptide, GE137, with a high in vitro affinity for the human c-Met protein, was tested in a panel of ovarian cancer cell lines. Finally, the feasibility of detecting submillimeter ovarian cancer cell peritoneal metastases in vivo was tested through the intravenous injection of GE137 into mice with tumor xenografts.
  
  
  RESULTS
  Using optical imaging it was possible to detect c-Met expression in submillimeter peritoneal metastases that were freshly excised from a human high-grade serous ovarian cancer. GE137 selectively bound to the c-Met tyrosine kinase without activating survival signaling pathways (AKT or extracellular signal-regulated kinase phosphorylation) downstream of c-Met. GE137 specifically accumulated in SKOv3 ovarian cancer cells expressing c-Met via clathrin-mediated endocytosis and emitted a fluorescent signal that lasted for at least 8 hours in tumor xenografts in vivo with a sustained high signal-to-noise ratio.
  
  
  CONCLUSIONS
  Our results suggest that intraoperative optical imaging could provide a new paradigm for selecting cancer patients for appropriate targeted therapies, particularly after initial chemotherapy.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Nuffield Department of Obstetrics and Gynaeoclogy, Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom; Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Davide
authors.initials: D
authors.lastname: Volpi
authors.forename: Muna
authors.initials: M
authors.lastname: El-Kasti
authors.forename: Daniel
authors.initials: D
authors.lastname: Klotz
authors.forename: Iain
authors.initials: I
authors.lastname: Tullis
authors.forename: Andrea
authors.initials: A
authors.lastname: Henricks
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.forename: Kevin
authors.initials: K
authors.lastname: Myers
authors.forename: Alex
authors.initials: A
authors.lastname: Laios
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.forename: Sunanda
authors.initials: S
authors.lastname: Dhar
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.forename: Ahmed Ashour
authors.initials: AA
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D005260:Female; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy / Q000379:methods; D061848:Optical Imaging / Q000379:methods*; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000601:surgery* / Q000628:therapy; D010456:Peptides, Cyclic / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000556:secondary*; D057285:Precision Medicine; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D005456:Fluorescent Dyes; C000595832:GE137 peptide; C000715470:MAS1 protein, human; D010456:Peptides, Cyclic; D000090063:Proto-Oncogene Mas; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met; fluorescence imaging; minimal residual disease; operative imaging; optical imaging; ovarian cancer; personalized medicine; targeted therapy