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.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
Combination treatment of selumetinib/docetaxel was superior to the respective mono-therapies shown by PCC of PET and ADC in conjunction with histology.
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany.
Valerie S
VS
Honndorf
Department of Radiology, Diagnostic and Interventional Radiology, Eberhard Karls University, Tübingen, Germany.
Holger
H
Schmidt
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany.
Stefan
S
Wiehr
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany.
Hans F
HF
Wehrl
Institute for Pathology, Eberhard Karls University, Tübingen, Germany.
Leticia
L
Quintanilla-Martinez
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany.
Anke
A
Stahlschmidt
Personalized Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
Hervé
H
Barjat
Personalized Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK.
Sally-Ann
SA
Emmas
Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Tübingen, Germany. Bernd.Pichler@med.uni-tuebingen.de.
Bernd J
BJ
Pichler
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D015224:Dideoxynucleosides / Q000378:metabolism*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D000077143:Docetaxel; D004357:Drug Synergism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D015224:Dideoxynucleosides; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; C002854:alovudine
Apparent diffusion coefficient; Diffusion-weighted magnetic resonance imaging; Docetaxel; HCT 116 tumor xenograft mouse model; Pearson correlation coefficient; Positron emission tomography; Selumetinib; Treatment effect