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Preclinical Evaluation of a Novel c-Met Inhibitor in a Gastric Cancer Xenograft Model Using Small Animal PET

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Abstract

Purpose

Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) versus 3′-deoxy-3′-18F-fluorothymidine ([18F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.

Procedures

The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96 h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels.

Results

BAY 853474 significantly reduces tumor growth. [18F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [18F]FLT uptake in the tumor tissue was completely absent 96 h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals.

Conclusion

These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.

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Acknowledgments

We are grateful to Maren Koenig, Mareike Lehnhoff, Daniel Bukala, Nadine Bauer, Denis Lamparter and Monika Klotz, Elke Schmid, Kirsten Steiner-Hahn, Jenny Laube, Tanja Rose for expert technical assistance. The research was partially supported by the Deutsche Forschungsgemeinschaft SFB 773.

Disclosure of Potential Conflicts of Interest

Oliver von Ahsen, Lars Röse, and Andre Mueller are full-time employees of Bayer Healthcare.

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Authors and Affiliations

  1. Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Eberhard Karls University Tübingen, Tübingen, Germany

    Stefan Wiehr, Julia G. Mannheim, Valerie Honndorf, Damaris Kukuk, Gerald Reischl & Bernd J. Pichler

  2. Bayer Pharma AG, Berlin, Germany

    Oliver von Ahsen, Lars Röse & Andre Mueller

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  1. Stefan Wiehr
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Correspondence to Bernd J. Pichler.

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Wiehr, S., von Ahsen, O., Röse, L. et al. Preclinical Evaluation of a Novel c-Met Inhibitor in a Gastric Cancer Xenograft Model Using Small Animal PET. Mol Imaging Biol 15, 203–211 (2013). https://doi.org/10.1007/s11307-012-0580-0

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