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Evaluation of [18F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer

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Abstract

Purpose

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.

Procedures

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.

Results

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.

Conclusions

[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.

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Acknowledgments

The authors thank Philippe Joye and Caroline Berghmans of the Molecular Imaging Center Antwerp for their valuable technical assistance.

This work was funded by the University of Antwerp through a Bijzonder Onderzoeksfond (BOF27327). D.T. is funded by the Research Foundation Flanders (FWO) through a postdoctoral grant (1211313N). Si.S and C.V. are supported by the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution.

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Authors and Affiliations

  1. Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Sara Rapic, Christel Vangestel, Jeroen Verhaeghe, David Thomae, Tim Van den Wyngaert, Steven Staelens & Sigrid Stroobants

  2. Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Christel Vangestel, David Thomae, Tim Van den Wyngaert & Sigrid Stroobants

  3. Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Patrick Pauwels

  4. Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Patrick Pauwels

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  1. Sara Rapic
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Correspondence to Sigrid Stroobants.

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Rapic, S., Vangestel, C., Verhaeghe, J. et al. Evaluation of [18F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer. Mol Imaging Biol 19, 109–119 (2017). https://doi.org/10.1007/s11307-016-0974-5

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