Thomas Lindner1, Anastasia Loktev1,2,3, Annette Altmann1,2, Frederik Giesel1, Clemens Kratochwil1, Jürgen Debus4,5, Dirk Jäger6, Walter Mier1, Uwe Haberkorn7,2. 1. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany. 2. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. 4. Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany. 5. Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; and. 6. Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. 7. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany uwe.haberkorn@med.uni-heidelberg.de.
Abstract
Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is involved in a variety of tumor-promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance, and immunosuppression. Because FAP shows low expression in most normal organs, it presents an interesting target for imaging and endoradiotherapy. In this investigation, FAP inhibitors (FAPIs) were modified and optimized for use as theranostic tracers. Methods: FAPIs based on a quinoline structure were synthesized and characterized with respect to binding, internalization, and efflux in cells expressing human and murine FAP as well as CD26. Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. Results: Of 15 synthesized FAPIs, FAPI-04 was identified as the most promising tracer for clinical application. Compared with the previously published ligand, FAPI-02, FAPI-04 showed excellent stability in human serum, higher affinity for FAP as opposed to CD26, and slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals, leading to larger areas under the curve as calculated from biodistribution experiments. Finally, PET/CT scans with 68Ga-FAPI-04 in 2 patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction in pain symptoms after therapy with a considerably low dose of 90Y-FAPI-04. Conclusion: FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.
Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is involved in a variety of tumor-promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance, and immunosuppression. Because FAP shows low expression in most normal organs, it presents an interesting target for imaging and endoradiotherapy. In this investigation, FAP inhibitors (FAPIs) were modified and optimized for use as theranostic tracers. Methods: FAPIs based on a quinoline structure were synthesized and characterized with respect to binding, internalization, and efflux in cells expressing human and murineFAP as well as CD26. Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. Results: Of 15 synthesized FAPIs, FAPI-04 was identified as the most promising tracer for clinical application. Compared with the previously published ligand, FAPI-02, FAPI-04 showed excellent stability in human serum, higher affinity for FAP as opposed to CD26, and slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals, leading to larger areas under the curve as calculated from biodistribution experiments. Finally, PET/CT scans with 68Ga-FAPI-04 in 2 patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction in pain symptoms after therapy with a considerably low dose of 90Y-FAPI-04. Conclusion:FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer.
Authors: Thomas Lindner; Annette Altmann; Susanne Krämer; Christian Kleist; Anastasia Loktev; Clemens Kratochwil; Frederik Giesel; Walter Mier; Frederik Marme; Jürgen Debus; Uwe Haberkorn Journal: J Nucl Med Date: 2020-03-13 Impact factor: 10.057
Authors: Rudolf A Werner; Ralph A Bundschuh; Lena Bundschuh; Stefano Fanti; Mehrbod S Javadi; Takahiro Higuchi; Alexander Weich; Kenneth J Pienta; Andreas K Buck; Martin G Pomper; Michael A Gorin; Ken Herrmann; Constantin Lapa; Steven P Rowe Journal: J Nucl Med Date: 2019-02-22 Impact factor: 10.057
Authors: Frederik L Giesel; Claus Peter Heussel; Thomas Lindner; Manuel Röhrich; Hendrik Rathke; Hans-Ulrich Kauczor; Jürgen Debus; Uwe Haberkorn; Clemens Kratochwil Journal: Eur J Nucl Med Mol Imaging Date: 2019-05-22 Impact factor: 9.236
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Authors: Ken Herrmann; Markus Schwaiger; Jason S Lewis; Stephen B Solomon; Barbara J McNeil; Michael Baumann; Sanjiv S Gambhir; Hedvig Hricak; Ralph Weissleder Journal: Lancet Oncol Date: 2020-03 Impact factor: 41.316
Authors: An De Decker; Gwendolyn Vliegen; Dries Van Rompaey; Anke Peeraer; An Bracke; Line Verckist; Koen Jansen; Ruth Geiss-Friedlander; Koen Augustyns; Hans De Winter; Ingrid De Meester; Anne-Marie Lambeir; Pieter Van der Veken Journal: ACS Med Chem Lett Date: 2019-07-09 Impact factor: 4.345