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15.03.2016 | Original Article | Ausgabe 9/2016

European Journal of Nuclear Medicine and Molecular Imaging 9/2016

Mechanistic interrogation of combination bevacizumab/dual PI3K/mTOR inhibitor response in glioblastoma implementing novel MR and PET imaging biomarkers

Zeitschrift:
European Journal of Nuclear Medicine and Molecular Imaging > Ausgabe 9/2016
Autoren:
Philip J. O’Halloran, Thomas Viel, David W. Murray, Lydia Wachsmuth, Katrin Schwegmann, Stefan Wagner, Klaus Kopka, Monika A. Jarzabek, Patrick Dicker, Sven Hermann, Cornelius Faber, Tim Klasen, Michael Schäfers, David O’Brien, Jochen H. M. Prehn, Andreas H. Jacobs, Annette T. Byrne
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00259-016-3343-3) contains supplementary material, which is available to authorized users.
Philip J. O’Halloran, Thomas Viel and David W. Murray contributed equally to this work.
Andreas H. Jacobs and Annette T. Byrne are joint senior authors.

Abstract

Purpose

Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235.

Methods

Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET and O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry.

Results

Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [18F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [18F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts.

Conclusion

Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology.

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Zusatzmaterial
Supplementary Table 1 (PDF 104 kb)
259_2016_3343_MOESM1_ESM.pdf
Supplementary Table 2 (PDF 125 kb)
259_2016_3343_MOESM2_ESM.pdf
Supplementary Figure 1 Correlation between imaging and IHC data. a Correlation between MDI and microvessel density as determined by vWF staining. b Correlation between [18F]FET uptake and microvessel density as determined by vWF staining. c Correlation between MDI and [18F]FET uptake. d Correlation between [18F]FLT uptake and Ki67 index (PDF 143 kb)
259_2016_3343_MOESM3_ESM.pdf
Literatur
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