Abstract
Simple SummaryFAP-targeted radiotracers, recently introduced in cancer treatment, accumulate in Cancer-Associated Fibroblasts (CAFs). CAFs are present in tumor lesions but do not correspond to genuine cancer cells, although they behave in an abnormal and disease-promoting manner. One of their characteristic features, the expression of the surface protein FAP, can be utilized to discriminate between cancerous and healthy tissues. By the choice of an appropriate radionuclide, FAP-targeted tracers can be used for imaging or therapy in many cancer types. Therefore, the first successful application of FAP-targeted imaging has led to an enormous and growing interest in nuclear medicine and radiopharmacy.Targeting fibroblast activation protein (FAP) in cancer-associated fibroblasts (CAFs) has attracted significant attention in nuclear medicine. Since these cells are present in most cancerous tissues and FAP is rarely expressed in healthy tissues, anti-FAP tracers have a potential as pan-tumor agents. Compared to the standard tumor tracer [18F]FDG, these tracers show better tumor-to-background ratios (TBR) in many indications. Unlike [18F]FDG, FAP-targeted tracers do not require exhausting preparations, such as dietary restrictions on the part of the patient, and offer the possibility of radioligand therapy (RLT) in a theragnostic approach. Although a radiolabeled antibody was clinically investigated as early as the 1990s, the breakthrough event for FAP-targeting in nuclear medicine was the introduction and clinical application of the so-called FAPI-tracers in 2018. From then, the development and application of FAP-targeted tracers became hot topics for the radiopharmaceutical and nuclear medicine community, and attracted the interest of pharmaceutical companies. The aim of this review is to provide a comprehensive overview of the development of FAP-targeted radiopharmaceuticals and their application in nuclear medicine.
Highlights
Introduction iationsFibroblasts are present in almost all tissues and usually rest in a quiescent stage
In the course of the disease, these cancer-associated fibroblasts (CAFs) start to recruit other fibroblasts and become involved in many other functions, which are responsible for the malignancy of a tumor
This study showed that fibroblast activation protein (FAP)-targeting is potentially superior to [18 F]2-fluoro-2-deoxyglucose ([18 F]FDG) in PET imaging for many important tumor entities, such as breast, lung, head-and-neck or colorectal cancers [6]
Summary
The first account of clinical FAP-targeting, together with planar and SPECT imaging in 17 patients before surgery, was published in 1994. Welt et al reported that the 131 I-labeled monoclonal murine antibody mAb F19 was able to detect lesions of a diameter as small as 1 cm at 3–5 days after injection [9]. Due to the encouraging results, sibrotuzumab, a humanized version of mAb F19, was developed to address the issue of immune response to murine antibodies. A phase I clinical study used co-administered 131 I-labeled sibrotuzumab to evaluate pharmacokinetics. A 89 Zr-labeled antibody, which was originally identified by phage display, was used for PET/CT imaging in prostate cancer xenograft models. The best time point for imaging was at 3 days after injection, while tumor-to-background values decreased for some tissues afterwards. This lowers the dose absorbed by radiation sensitive bone marrow, while, the application of conjugates with cytotoxic drugs were recommended [12]
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