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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, Cu (half-life = 12.7 h) and Ac (half-life = 10 days), to label FAP inhibitors (FAPI) in mice with human pancreatic cancer xenografts. Male nude mice (body weight = 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, = 12; MIA PaCa-2, = 8). Tumor xenograft mice were investigated after the intravenous injection of Cu-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 Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice ( = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-alpha antibody. For radioligand therapy, Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice ( = 6). Tumor size was monitored and compared to that of control mice ( = 6). Dynamic imaging of Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of 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 Cu-FAPI-04 than Ga-FAPI-04, except in the heart, and excretion in the urine was higher for Ga-FAPI-04 than Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. Ac-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. This proof of concept study showed that Cu-FAPI-04 and 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.
This article was published in the following journal.
Name: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
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A gene product of the p16 tumor suppressor gene (GENES, P16). It antagonizes the function of MDM2 PROTEIN (which regulates P53 TUMOR SUPPRESSOR PROTEIN by targeting it for degradation). p14ARF is produced from the beta mRNA transcript of the p16 gene. The other gene product, produced from the alternatively spliced alpha transcript, is CYCLIN-DEPENDENT KINASE INHIBITOR P16. Both p16 gene products have tumor suppressor functions.
A B7 antigen subtype that inhibits the costimulation of T-cell activation, proliferation, cytokine production and development of cytotoxicity. The over expression of this protein in a variety of tumor cell types suggests its role in TUMOR IMMUNE EVASION.
A nuclear and cytoplasmic protein that associates with KINETOCHORES and contains a C-terminal TUDOR DOMAIN. It plays a critical role in the cellular response to DNA DAMAGE and localizes to DOUBLE-STRAND DNA BREAKS. It may also function in M PHASE CELL CYCLE CHECKPOINTS and as an enhancer of TUMOR SUPPRESSOR PROTEIN P53-mediated transcriptional activation.
A single-chain polypeptide growth factor that plays a significant role in the process of WOUND HEALING and is a potent inducer of PHYSIOLOGIC ANGIOGENESIS. Several different forms of the human protein exist ranging from 18-24 kDa in size due to the use of alternative start sites within the fgf-2 gene. It has a 55 percent amino acid residue identity to FIBROBLAST GROWTH FACTOR 1 and has potent heparin-binding activity. The growth factor is an extremely potent inducer of DNA synthesis in a variety of cell types from mesoderm and neuroectoderm lineages. It was originally named basic fibroblast growth factor based upon its chemical properties and to distinguish it from acidic fibroblast growth factor (FIBROBLAST GROWTH FACTOR 1).
A member of the family of TISSUE INHIBITOR OF METALLOPROTEINASES. It is a 21-kDa nonglycosylated protein found in tissue fluid and is secreted as a complex with progelatinase A by human fibroblast and uncomplexed from alveolar macrophages. An overexpression of TIMP-2 has been shown to inhibit invasive and metastatic activity of tumor cells and decrease tumor growth in vivo.
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