Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model
Yuwei Liu, Tadashi Watabe, Kazuko Kaneda‐Nakashima, Yoshifumi Shirakami, Sadahiro Naka, Kazuhiro Ooe, Atsushi Toyoshima, Kojiro Nagata, Uwe Haberkorn, Clemens Kratochwil, Atsushi Shinohara, Jun Hatazawa, Frederik L. Giesel
Abstract
Abstract Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64 Cu and 225 Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter ( 177 Lu)-labelled FAPI-46 and alpha-emitter ( 225 Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice ( n = 9) after the administration of [ 18 F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq ( n = 6), 10 MBq ( n = 6), 30 MBq ( n = 6), control ( n = 4) for [ 177 Lu]FAPI-46, and 3 kBq ( n = 3), 10 kBq ( n = 2), 30 kBq ( n = 6), control ( n = 7) for [ 225 Ac]FAPI-46. Tumour sizes and body weights were followed. Results [ 18 F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [ 177 Lu]FAPI-46 and [ 225 Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [ 177 Lu]FAPI-46 were relatively slow but lasted longer than those of [ 225 Ac]FAPI-46. Conclusion This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.