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The Synergistic Effect of Selumetinib/Docetaxel Combination Therapy Monitored by [18 F]FDG/[18 F]FLT PET and Diffusion-Weighted Magnetic Resonance Imaging in a Colorectal Tumor Xenograft Model

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Abstract

Purpose

Positron emission tomography (PET) and diffusion-weighted MRI (DW-MRI) were used to characterize the treatment effects of the MEK1/2 inhibitor selumetinib (AZD6244), docetaxel, and their combination in HCT116 tumor-bearing mice on the molecular level.

Procedures

Mice were treated with vehicle, selumetinib (25 mg/kg), docetaxel (15 mg/kg), or a combination of both drugs for 7 days and imaged at four time points with 2-deoxy-2-[18 F]fluoro-D-glucose ([18 F]FDG) or 3′-deoxy-3′-[18 F]fluorothymidine ([18 F]FLT) followed by DW-MRI to calculate the apparent diffusion coefficient (ADC). Data was cross-validated using the Pearson correlation coefficient (PCC) and compared to histology (IHC).

Results

Each drug led to tumor growth inhibition but their combination resulted in regression. Separate analysis of PET or ADC could not provide significant differences between groups. Only PCC combined with IHC analysis revealed the highest therapeutic impact for combination therapy.

Conclusion

Combination treatment of selumetinib/docetaxel was superior to the respective mono-therapies shown by PCC of PET and ADC in conjunction with histology.

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Acknowledgments

This work was partially funded by AstraZeneca. We also acknowledge funding by the Swiss Werner Siemens-Foundation, Germany Ministry for Education and Research (BMBF 01GQ1415), University of Tuebingen (fortüne 21-01-0-0 and 2209-0-0) and the European Seventh Framework Programme (No: 602646). We would like to thank Maren Koenig and Daniel Bukala for their excellent support performing the imaging studies and Walter Ehrlichmann for the tracer production.

Conflict of Interest

Bernd Pichler received grant/research support from Siemens, AstraZeneca, Bayer Healthcare, Boehringer-Ingelheim, Oncodesign, Merck, Bruker. Hervé Barjat and Sally-Ann Emmas are employees and shareholders of AstraZeneca. Other authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany

    Valerie S. Honndorf, Stefan Wiehr, Hans F. Wehrl, Anke Stahlschmidt & Bernd J. Pichler

  2. Department of Radiology, Diagnostic and Interventional Radiology, Eberhard Karls University, Tübingen, Germany

    Holger Schmidt

  3. Institute for Pathology, Eberhard Karls University, Tübingen, Germany

    Leticia Quintanilla-Martinez

  4. Personalized Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK

    Hervé Barjat & Sally-Ann Emmas

Authors
  1. Valerie S. Honndorf
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  2. Holger Schmidt
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  3. Stefan Wiehr
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  4. Hans F. Wehrl
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  6. Anke Stahlschmidt
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  7. Hervé Barjat
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  9. Bernd J. Pichler
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Corresponding author

Correspondence to Bernd J. Pichler.

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Honndorf, V.S., Schmidt, H., Wiehr, S. et al. The Synergistic Effect of Selumetinib/Docetaxel Combination Therapy Monitored by [18 F]FDG/[18 F]FLT PET and Diffusion-Weighted Magnetic Resonance Imaging in a Colorectal Tumor Xenograft Model. Mol Imaging Biol 18, 249–257 (2016). https://doi.org/10.1007/s11307-015-0881-1

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  • DOI: https://doi.org/10.1007/s11307-015-0881-1

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