Fibroblast activation protein targeted therapy using [¹⁷⁷Lu]FAPI-46 compared with [²²⁵Ac]FAPI-46 in a pancreatic cancer model.

Abstract

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 ⁶⁴Cu and ²²⁵Ac-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 (¹⁷⁷Lu)-labelled FAPI-46 and alpha-emitter (²²⁵Ac)-labelled FAPI-46 in pancreatic cancer models. PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [¹⁸F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [¹⁷⁷Lu]FAPI-46 and [²²⁵Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [¹⁷⁷Lu]FAPI-46 and [²²⁵Ac]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 [¹⁷⁷Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [²²⁵Ac]FAPI-46. Tumour sizes and body weights were followed. [¹⁸F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [¹⁷⁷Lu]FAPI-46 and [²²⁵Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [¹⁷⁷Lu]FAPI-46 and [²²⁵Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [¹⁷⁷Lu]FAPI-46 were relatively slow but lasted longer than those of [²²⁵Ac]FAPI-46. 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.