RT Journal Article
SR Electronic
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
FD Society of Nuclear Medicine
SP jnumed.119.233122
DO 10.2967/jnumed.119.233122
A1 Watabe, Tadashi
A1 Liu, Yuwei
A1 Kaneda-Nakashima, Kazuko
A1 Shirakami, Yoshifumi
A1 Lindner, Thomas
A1 Ooe, Kazuhiro
A1 Toyoshima, Atsushi
A1 Nagata, Kojiro
A1 Shimosegawa, Eku
A1 Haberkorn, Uwe
A1 Kratochwil, Clemens
A1 Shinohara, Atsushi
A1 Giesel, Frederik
A1 Hatazawa, Jun
YR 2019
UL http://jnm.snmjournals.org/content/early/2019/10/03/jnumed.119.233122.abstract
AB 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.