Hence, FAP presents an ideal pan-cancer target structure for imaging and targeted delivery of therapeutics. It opens up new applications for non-invasive tumor visualization, staging examinations, and radioligand therapy for many cancers that have not yet been covered by nuclear theranostics and can be poorly treated by other therapies. In fact, besides thyroid cancer currently prostate cancer and neuroendocrine tumors are its predominant beneficiaries. “Targeting FAP to deplete stromal CAFs may disrupt cancer supportive functions and inhibit cancer growth. Furthermore, by breaking the stroma barrier, the effectiveness of other pharmacologic, immunologic, radiation- or cell-based systemic therapies may thus be enhanced.”[ii] So much about the lock. The challenge lies in developing a suitable key.

Tracers

FAP-specific inhibitors were first developed in the early 2000s as anticancer drugs, such as sibrotuzumab or talabostat. Inhibitor-based radiopharmaceuticals are the next step. Scientists are intensively working on the development of a theranostic tracer that can be employed for both diagnostics and therapy; that is, be labelled with an imaging or therapeutic isotope (e.g. gallium-68 ⁶⁸Ga or lutetium-177 ¹⁷⁷Lu respectively), dock to FAP upon being injected and stay there long enough to produce the desired effect.

Imaging

The Heidelberg University has recently developed a quinoline-based FAP inhibitor (FAPI) to enable radiolabeling. First human studies of 68Ga-FAPI-04 demonstrated high uptake in the tumor and low – in the surrounding healthy tissues (so-called tumor-to-background ratio) resulting in high-contrast tumor imaging across various cancers. All patients tolerated the examination really well, no pharmacologic or physiologic responses were observed, no symptoms reported. FDG (fluorodeoxy-D-glucose) tracer depends on blood sugar and requires prior fasting (6 hours min) and reclining for 1 hour during the uptake phase. FAPI PET/CT will significantly simplify the clinical workflow because it requires no preparation, and the patient is ready for scanning in 10 min after the injection. The same reliance of FDG on glucose metabolism results in many false-positive images while staging cancers due to its high uptake in highly glycolytic healthy (e.g. brain, muscles or gut) or inflammatory tissues (e.g. lymph nodes). With the tumor stroma making 90% of the tumor volume, stroma-targeted FAPI PET imaging may be more sensitive in detecting small cancer lesions.

Radioligand therapy

Whereas the tumor uptake of the radiopharmaceutical is more important for diagnostic means, retention time of the tracer in the fibroblast becomes crucial for the therapeutic ends. The radiation emitter must stay in the cell long enough for it to cause an effect, i.e. destroy the cell. FAPI-04 washes out of the tumor tissue relatively rapidly and limits the delivery of the radiation dose of the common therapeutic emitters, like lutetium or actinium. Alternatively, “the physical half-life of the therapeutic isotope needs to be matched to the tumor retention time.”[ii]

Limitations

Despite FAPI excellent tumor-to-background contrast ratios ranging from blood to liver to muscles to intestines, FAP expression is not exclusively cancer-specific. It still shows in some non-cancerous tissues, whenever fibroblasts become activated, for example “in remodelling processes such as wound healing, inflammation, or fibrosis”[ii].

Conclusion

Many cancers “tend to grow in an invasive and diffuse manner infiltrating the adjacent often delicate and anatomically complex structures”[i] FAPI-based imaging and radiotherapy will constitute a quantum leap in pan-cancer nuclear theranostics. It will enable higher precision in diagnostics and treatment of many cancer types. Scientists continue tinkering on the tracer to optimize the uptake and retention. Tests with a variant FAPI-46 have been encouraging. Another novel compound has also showed promising results in patients with iodine refractory thyroid cancer and demonstrated significantly longer retention of over several days in the tumor and metastases.[iii] These are the latest, but for sure not the last tracer derivatives. Stay tuned.