Science and Research

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: (64)Cu- and (225)Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, (64)Cu (half-life, 12.7 h) and (225)Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) 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 (64)Cu-FAPI-04 (7.21 +/- 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of (68)Ga-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, (225)Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of (64)Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of (64)Cu-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 (64)Cu-FAPI-04 than for (68)Ga-FAPI-04, except in the heart, and excretion in the urine was higher for (68)Ga-FAPI-04 than for (64)Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. (225)Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that (64)Cu-FAPI-04 and (225)Ac-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.

  • Watabe, T.
  • Liu, Y.
  • Kaneda-Nakashima, K.
  • Shirakami, Y.
  • Lindner, T.
  • Ooe, K.
  • Toyoshima, A.
  • Nagata, K.
  • Shimosegawa, E.
  • Haberkorn, U.
  • Kratochwil, C.
  • Shinohara, A.
  • Giesel, F.
  • Hatazawa, J.

Keywords

  • *actinium
  • *fibroblast activation protein
  • *pancreatic cancer
  • *theranostics
  • *alpha-therapy
Publication details
DOI: 10.2967/jnumed.119.233122
Journal: J Nucl Med
Pages: 563-569 
Number: 4
Work Type: Original
Location: TLRC
Disease Area: LC
Partner / Member: DKFZ, UKHD
Access-Number: 31586001
See publication on PubMed

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