@article{2292b3d56199427588d74aee1ca9faff,
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.",
keywords = "ADC, DCE-MRI, PI3K inhibition, biomarker, diffusion weighted MRI, treatment monitoring",
author = "J. Cebulla and Huuse, {E. M.} and K. Pettersen and {Van Der Veen}, A. and E. Kim and S. Andersen and Prestvik, {W. S.} and Bofin, {A. M.} and Pathak, {A. P.} and G. Bj{\o}rk{\o}y and Bathen, {T. F.} and Moestue, {S. A.}",
note = "Funding Information: Animals were housed in the Comparative Medicine Core Facility, Norwegian University of Science and Technology (NTNU). In vivo MRI was performed at the MR Core Facility, NTNU. Paraffin embedding, sample sectioning and HES staining were performed at the CMIC Core Facility, NTNU. Ex vivo MRI was performed at the BRB Molecular Imaging Service Center, The Johns Hopkins University. Micro-CT imaging was performed by Numira Biosciences (Salt Lake City, UT, USA). We thank Elise Sandsmark for help with the acquisition of images of HES-stained tumour sections. The research was supported by a Leiv Eiriksson mobility stipend (224788/F11) from the Norwegian Research Council and a Travel and Research Grant from the Norwegian Research School in Medical Imaging (MedIm) to JC; student grants to AvdV from the Dutch VSB fonds and Prins Bernhard cultuurfonds (Klok Korsmit Tacke fonds); a Susan G. Komen for the Cure Career Catalyst Grant (KG090640) to APP; a grant from the Norwegian Cancer Society and the Norwegian Breast Cancer Society (2209215-2011) to SAM; grants from the Norwegian Cancer Society (171656–PR-2009-0270) and The Cancer Research Foundation at St Olav{\textquoteright}s University Hospital to GB. Publisher Copyright: {\textcopyright} 2015 Cancer Research UK. All rights reserved 0007 - 0920/15.",
year = "2015",
month = feb,
day = "3",
doi = "10.1038/bjc.2014.628",
language = "English (US)",
volume = "112",
pages = "504--513",
journal = "British journal of cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "3",
}