Imaging Cancer-Associated Fibroblasts (CAFs) with FAPi PET

Abstract

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells’ proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on the cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have recently been developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments regarding radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors, such as primary liver and gastro-entero-pancreatic cancer, or in regions with an unfavorable tumor-to-background ratio at FDG-PET/CT (i.e., brain), and in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at present, and definitive conclusions about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center prospective studies powered for efficacy are needed.

Emerging Role of FAPI PET Imaging for the Assessment of Benign Bone and Joint Diseases

“…In this scenario, the role of FAPI PET/CT for the evaluation of cancer has been evaluated in several studies and the preliminary results are promising, as it also seems to allow the evaluation of tumors with low [ 18 F]FDG uptake. Interestingly, when coupled together, [ 18 F]FDG and radiolabeled FAPI are able to better define and comprehend tumoral metabolic heterogeneity [ 10 , 13 , 14 , 15 , 16 ].…”

The role of [99mTc]Tc-HFAPi SPECT/CT in patients with malignancies of digestive system: first clinical experience

“…Recent PET/CT studies with FAP inhibitors have been well developed, revealing strong PET signals across dozens of major cancers, especially digestive system cancers [6,7,19,20]. With FAPI-specific PET imaging, patients do not require dietary preparation, and high-quality images can be obtained soon after tracer injection (10 min to 1 h, mainly 1 h) [21]. The superior value of [ 68 Ga]Ga-FAPI PET/CT over [ 18 F]FDG in detecting primary and metastatic lesions in digestive system cancers has been confirmed, most lesions showing higher tracer uptake with FAPI imaging, and it exhibits a promising role in the diagnosis, (re)staging, management, and treatment planning of digestive system cancers [22].…”

The prognostic marker elastin correlates with epithelial–mesenchymal transition and vimentin‐positive fibroblasts in gastric cancer

“…Fibroblasts accumulate in the TME and contribute to the emergence and progression of GC [ 19 , 20 ]. This not only provides abundant growth factors for stromal components of the TME and promotes the proliferation of cancer cells but also creates a suitable physical environment for lymphatic metastasis and blood metastasis of cancer cells [ 21 , 22 , 23 ].…”