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IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein–specific PET/CT

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Abstract

Purpose

Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used 68Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas).

Methods

For binding studies with 177Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with 68Ga-labeled compounds followed by small-animal PET imaging and 177Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of 68Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody.

Results

FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma.

Conclusions

Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.

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Funding

This work was funded by the Federal Ministry of Education and Research, grant number 13N 13341.

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Authors and Affiliations

  1. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Manuel Röhrich, Anastasia Loktev, Annette Altmann, Paul Flechsig, Thomas Lindner & Uwe Haberkorn

  2. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany

    Manuel Röhrich, Annette Altmann & Uwe Haberkorn

  3. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Annika K. Wefers & Andreas von Deimling

  4. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Annika K. Wefers & Andreas von Deimling

  5. Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Daniel Paech

  6. Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany

    Sebastian Adeberg, Paul Windisch, Julius P. Schuster, Peter E. Huber & Jürgen Debus

  7. Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Hielscher

  8. Division of Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Ralf Floca

  9. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany

    Dominik Leitz & Uwe Haberkorn

  10. Clinical Cooperation Unit Molecular Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Julius P. Schuster & Peter E. Huber

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  1. Manuel Röhrich
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Contributions

Experimental design: AL, MR, TL, AA, and UH; preclinical experiments: AL, TL, AA, and MR; clinical studies: MR, SA, PW, PF, and JD; PET/MRI co-registration studies: DP, MR, and RF; statistical analysis: TH; immunohistochemistry: PEH, JPS, AW, and AVD. All authors have seen and approved the manuscript.

Corresponding author

Correspondence to Manuel Röhrich.

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Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval of animal experiments

The animal experiments of this work were approved by the local ethics committee and all applicable international, national, and institutional guidelines for the care and use of animals were followed.

Ethical approval of clinical studies

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients signed written informed consent. The evaluation was approved by our institutional ethical review board (no. S-016/2018).

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Manuel Röhrich, Anastasia Loktev, Thomas Lindner, and Uwe Haberkorn are co-authors.

This article is part of the Topical Collection on Oncology – Brain

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Röhrich, M., Loktev, A., Wefers, A.K. et al. IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein–specific PET/CT. Eur J Nucl Med Mol Imaging 46, 2569–2580 (2019). https://doi.org/10.1007/s00259-019-04444-y

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