Fibroblast activation protein (FAP) and PET

The fibroblast activation protein is an atypical type II transmembrane serine protease, having both dipeptidyl peptidase and endopeptidase activities. FAP is a member of a large superfamily of serine hydrolases (>200 genes in humans) that contains a number of enzymes relevant to metabolic diseases. FAP is closely related to dipeptidyl peptidase 4 (DPP-4). FAP expression in healthy tissue of adults is low, but it is expressed on activated fibroblasts, for instance during wound healing. Small amounts of FAP also circulates in an active form in plasma. Fibroblasts express FAP also during chronic inflammation, atherosclerosis, and fibrosis (Hamson et al., 2014). Cancer-associated fibroblasts (CAFs) overexpress FAP, promoting tumour cell migration and angiogenesis. FAP is a very promising target in the theranostics of various tumour types, and in assessment of inflammatory diseases.

Fibroblast activation protein inhibitor (FAPI)

Isotope-labelled FAP inhibitors (FAPIs) have been developed for diagnostic and theranostic use (Dendl et al., 2021). Small-molecule FAPI radioligands are internalized after binding. Those may provide good tumour lesion detection from a short and early (∼10 min) PET scan, increasing the scan volume in clinical work (Fernandus et al., 2021). 68Ga-labelled FAPI-04 has low nanomolar affinity, an almost complete internalization of more than 90%, and rapid blood clearance. Tumour-to-background ratio is better with [68Ga]FAPI than with [18F]FDG in organs where physiological [18F]FDG uptake is high (Giesel et al., 2021). SUVmax ranges of benign lesions and malignant tumours overlap, but lesions can usually be differentiated by combining CT and clinical data (Zheng et al., 2021) and with carefully defined cutoff values (Dabir et al., 2023). Tumour-to-blood ratio correlates well with 2TCM-derived VT, and better than SUVmax or SUVmean (Chen et al., 2023). Despite of almost complete internalization of [68Ga]FAPI-04 in fibroblasts, reversible 2-tissue compartmental model and Logan plot (using whole blood as input function) have been found to fit the dynamic PET data better than irreversible compartmental model and Patlak plot (Geist et al., 2021; Chen et al., 2023).

OncoFAP is a modified version of FAPI-04 with even higher, subnanomolar affinity to FAP (Millul et al., 2021). [68Ga]OncoFAP has shown high uptake in tumours and rapid clearance from healthy tissues (Backhaus et al., 2022). BiOncoFAP has dimeric FAP-binding motif, leading to longer tumour residence time, and [177Lu]BiOncoFAP has shown favourable tumour-to-organ ratios (Galbiati et al., 2022).

[68Ga]FAPI-46 biodistribution (SUV at ∼60 min) correlates strongly with FAP expression across multiple cancers, suggesting that FAPI PET could be used as a pancancer FAP marker and as a stratification tool for FAP-targeted therapies (Mona et al., 2022).

See also:


Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 2014; 8(5-6): 454-463. doi: 10.1002/prca.201300095.

Schmidkonz C, Kuwert T, Atzinger A, Cordes M, Schett G, Ramming A, Götz T. Fibroblast activation protein inhibitor imaging in nonmalignant diseases: a new perspective for molecular imaging. J Nucl Med. 2022; 63(12): 1786-1792. doi: 10.2967/jnumed.122.264205.

Verhulst E, Garnier D, De Meester I, Bauvois B. Validating cell surface proteases as drug targets for cancer therapy: what do we know, and where do we go? Cancers (Basel) 2022; 14(3): 624. doi: 10.3390/cancers14030624.

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Updated at: 2024-02-17
Created at: 2022-12-16
Written by: Vesa Oikonen