MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

J. Cebulla, E. M. Huuse, K. Pettersen, A. Van Der Veen, E. Kim, S. Andersen, W. S. Prestvik, A. M. Bofin, Arvind Pathak, G. Bjørkøy, T. F. Bathen, S. A. Moestue

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)504-513
Number of pages10
JournalBritish Journal of Cancer
Volume112
Issue number3
DOIs
StatePublished - Feb 3 2015

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1-Phosphatidylinositol 4-Kinase
Phosphatidylinositol 3-Kinases
Heterografts
Ovarian Neoplasms
Blood Vessels
Magnetic Resonance Imaging
Diffusion Magnetic Resonance Imaging
dactolisib
Biomarkers
Tomography
Water
Therapeutics

Keywords

  • ADC
  • biomarker
  • DCE-MRI
  • diffusion weighted MRI
  • PI3K inhibition
  • treatment monitoring

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity. / Cebulla, J.; Huuse, E. M.; Pettersen, K.; Van Der Veen, A.; Kim, E.; Andersen, S.; Prestvik, W. S.; Bofin, A. M.; Pathak, Arvind; Bjørkøy, G.; Bathen, T. F.; Moestue, S. A.

In: British Journal of Cancer, Vol. 112, No. 3, 03.02.2015, p. 504-513.

Research output: Contribution to journalArticle

Cebulla, J, Huuse, EM, Pettersen, K, Van Der Veen, A, Kim, E, Andersen, S, Prestvik, WS, Bofin, AM, Pathak, A, Bjørkøy, G, Bathen, TF & Moestue, SA 2015, 'MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity', British Journal of Cancer, vol. 112, no. 3, pp. 504-513. https://doi.org/10.1038/bjc.2014.628
Cebulla, J. ; Huuse, E. M. ; Pettersen, K. ; Van Der Veen, A. ; Kim, E. ; Andersen, S. ; Prestvik, W. S. ; Bofin, A. M. ; Pathak, Arvind ; Bjørkøy, G. ; Bathen, T. F. ; Moestue, S. A. / MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity. In: British Journal of Cancer. 2015 ; Vol. 112, No. 3. pp. 504-513.
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T1 - MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

AU - Cebulla, J.

AU - Huuse, E. M.

AU - Pettersen, K.

AU - Van Der Veen, A.

AU - Kim, E.

AU - Andersen, S.

AU - Prestvik, W. S.

AU - Bofin, A. M.

AU - Pathak, Arvind

AU - Bjørkøy, G.

AU - Bathen, T. F.

AU - Moestue, S. A.

PY - 2015/2/3

Y1 - 2015/2/3

N2 - 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.

AB - 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.

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