Evaluation of [18F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer.
In oncology, positron emission tomography imaging using dedicated tracers as biomarkers may assist in early evaluation of therapy efficacy. Using 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), we investigated the early effects of chemotherapeutic treatment on cancer cell proliferation in a BRAF-mutated colorectal cancer xenograft model.



Colo205 subcutaneously inoculated animals underwent 90-min dynamic imaging before and 24 h after treatment with vehicle (control), cetuximab (resistant) or irinotecan (sensitive). Total distribution volume was quantified from dynamic data, and standardized uptake values as well as tumor-to-blood ratios were calculated from static images averaged over the last 20 min. In vivo imaging data was correlated with ex vivo proliferation and thymidine metabolism proteins.



All imaging parameters showed a significant post-treatment decrease from [18F]FLT baseline uptake for the irinotecan group (p ≤ 0.001) as compared with the cetuximab and vehicle group and correlated strongly with each other (p ≤ 0.0001). In vivo data were in agreement with Ki67 staining, showing a significantly lower percentage of Ki67-positive cells in the irinotecan group as compared with other groups (p ≤ 0.0001). Tumor expression of thymidine kinase 1 phosphorylated on serine 13, thymidylate synthase, and thymidine phosphorylase remained unaffected, while thymidine kinase 1 expression was, surprisingly, significantly higher in irinotecan-treated animals (p ≤ 0.01). In contrast, tumor ATP levels were lowest in this group.



[18F]FLT positron emission tomography was found to be a suitable biomarker of early tumor response to anti-proliferative treatment, with static imaging not being inferior to full compartmental analysis in our xenograft model. The dynamics of thymidine kinase 1 protein expression and protein activity in low ATP environments merits further investigation.
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Sara
S
Rapic
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Christel
C
Vangestel
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Jeroen
J
Verhaeghe
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
David
D
Thomae
Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Patrick
P
Pauwels
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.
Tim
T
Van den Wyngaert
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Steven
S
Staelens
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Sigrid.Stroobants@uza.be.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. Sigrid.Stroobants@uza.be.
Sigrid
0000-0002-1285-9117
S
Stroobants
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000737:chemistry* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007700:Kinetics; D008819:Mice, Nude; D015203:Reproducibility of Results; D013936:Thymidine / Q000737:chemistry* / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000378:metabolism
D014408:Biomarkers, Tumor; D015224:Dideoxynucleosides; D000255:Adenosine Triphosphate; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine; D013936:Thymidine
18F-fluorothymidine; Colorectal cancer; Kinetic modeling; Positron emission tomography; Proliferation