TY - JOUR T1 - Theranostics targeting fibroblast activation protein in the tumor stroma: <sup>64</sup>Cu and <sup>225</sup>Ac labelled FAPI-04 in pancreatic cancer xenograft mouse models JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.119.233122 SP - jnumed.119.233122 AU - Tadashi Watabe AU - Yuwei Liu AU - Kazuko Kaneda-Nakashima AU - Yoshifumi Shirakami AU - Thomas Lindner AU - Kazuhiro Ooe AU - Atsushi Toyoshima AU - Kojiro Nagata AU - Eku Shimosegawa AU - Uwe Haberkorn AU - Clemens Kratochwil AU - Atsushi Shinohara AU - Frederik Giesel AU - Jun Hatazawa Y1 - 2019/10/01 UR - http://jnm.snmjournals.org/content/early/2019/10/03/jnumed.119.233122.abstract N2 - Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Owing to its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, 64Cu (half-life = 12.7 h) and 225Ac (half-life = 10 days), to label FAP inhibitors (FAPI) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight = 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of 64Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h post injection). Static scans 1 h after the injection of 68Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-alpha antibody. For radioligand therapy, 225Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared to that of control mice (n = 6). Results: Dynamic imaging of 64Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of 64Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for 64Cu-FAPI-04 than 68Ga-FAPI-04, except in the heart, and excretion in the urine was higher for 68Ga-FAPI-04 than 64Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. 225Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice compared to the control mice, without a significant change in body weight. Conclusion: This proof of concept study showed that 64Cu-FAPI-04 and 225Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. Alpha therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy. ER -