Fap-KO Mouse

Fibroblast activation protein (FAP), an atypical type II transmembrane serine protease, has both endopeptidase and post-proline dipeptidyl peptidase activities. It is highly expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment of many solid cancers, where it can modulate the microenvironment by remodeling the extracellular matrix (ECM). FAP is rarely expressed in healthy adult tissues but is upregulated in sites of tissue remodeling, such as in fibrosis, atherosclerosis, arthritis, and embryonic tissues [3].

Preclinical studies on FAP-2286, a FAP-binding peptide coupled to a radionuclide chelator, have shown its potential for radionuclide imaging and therapy. Biodistribution studies in mice demonstrated rapid and persistent uptake of radiolabeled FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 also exhibited antitumor activity in FAP-expressing tumors with no significant weight loss [1]. PET imaging using 68Ga-FAP-2286 has shown improved lesion detectability compared to 18F-FDG in various cancer types, including gastric, pancreatic, and hepatic cancers [4]. Targeting FAP with CAR-T cells is a strategy being explored to overcome the challenges of the tumor microenvironment in solid-tumor treatment. Preclinical studies and clinical trials of anti-FAP-CAR-T cells are underway, with efforts to optimize their cytotoxic efficiency in solid tumors [2].

In summary, FAP is a key molecule in the tumor microenvironment, with its overexpression associated with poor prognosis in various cancers. The use of preclinical models, such as mice in biodistribution and efficacy studies, has been crucial in understanding its role and developing targeted therapies. These findings suggest that targeting FAP could be a promising approach for cancer diagnosis, staging, and treatment [1,2,4].

References:

1. Zboralski, Dirk, Hoehne, Aileen, Bredenbeck, Anne, Smerling, Christiane, Osterkamp, Frank. 2022. Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy. In European journal of nuclear medicine and molecular imaging, 49, 3651-3667. doi:10.1007/s00259-022-05842-5. https://pubmed.ncbi.nlm.nih.gov/35608703/

2. Bughda, Reyisa, Dimou, Paraskevi, D'Souza, Reena R, Klampatsa, Astero. 2021. Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma. In ImmunoTargets and therapy, 10, 313-323. doi:10.2147/ITT.S291767. https://pubmed.ncbi.nlm.nih.gov/34386436/

3. Hamson, Elizabeth J, Keane, Fiona M, Tholen, Stefan, Schilling, Oliver, Gorrell, Mark D. 2014. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. In Proteomics. Clinical applications, 8, 454-63. doi:10.1002/prca.201300095. https://pubmed.ncbi.nlm.nih.gov/24470260/

4. Pang, Yizhen, Zhao, Liang, Meng, Tinghua, Sun, Long, Chen, Haojun. 2022. PET Imaging of Fibroblast Activation Protein in Various Types of Cancer Using 68Ga-FAP-2286: Comparison with 18F-FDG and 68Ga-FAPI-46 in a Single-Center, Prospective Study. In Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 64, 386-394. doi:10.2967/jnumed.122.264544. https://pubmed.ncbi.nlm.nih.gov/36215571/