title: MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity.
abstract: BACKGROUND
  The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity.
  
  
  METHODS
  The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg(-1), 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology.
  
  
  RESULTS
  The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found.
  
  
  CONCLUSIONS
  Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235.
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Cebulla
authors.affiliation: 1] Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway [2] Department of Medical Imaging, St Olavs University Hospital, Trondheim 7006, Norway.
authors.forename: E M
authors.initials: EM
authors.lastname: Huuse
authors.affiliation: 1] Center of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway [2] Department of Technology, University College of Sør-Trøndelag, Trondheim 7006, Norway [3] Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim 7006, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Pettersen
authors.affiliation: Center of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: A
authors.initials: A
authors.lastname: van der Veen
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.affiliation: 1] Center of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway [2] Department of Technology, University College of Sør-Trøndelag, Trondheim 7006, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Andersen
authors.affiliation: Department of Technology, University College of Sør-Trøndelag, Trondheim 7006, Norway.
authors.forename: W S
authors.initials: WS
authors.lastname: Prestvik
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim 7006, Norway.
authors.forename: A M
authors.initials: AM
authors.lastname: Bofin
authors.affiliation: Russell H Morgan Department of Radiology and Radiological Science and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Pathak
authors.affiliation: 1] Center of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway [2] Department of Technology, University College of Sør-Trøndelag, Trondheim 7006, Norway.
authors.forename: G
authors.initials: G
authors.lastname: Bjørkøy
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway.
authors.forename: T F
authors.initials: TF
authors.lastname: Bathen
authors.affiliation: 1] Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway [2] Department of Medical Imaging, St Olavs University Hospital, Trondheim 7006, Norway.
authors.forename: S A
authors.initials: SA
authors.lastname: Moestue
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011804:Quinolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; D019869:Phosphatidylinositol 3-Kinases; C531198:dactolisib