Bladder cancer has a variable incidence worldwide, changing with environmental factors. Urothelial carcinoma the the most common histopathological subtype. Early-stage bladder cancer has a favoruable prognosis, despite high survival rates (5years survival rate 40-70%). Advanced stage, however, has a very poor prognosis, with high metastatic rate. In these patients, several agents have been tried to improve outcomes. Radionuclide therapies gained importance in multiple cancer types, including prostate carcinoma, with recent reports proving its efficacy in especially metastatic, inoperable, advanced stage disease (1-4). In advanced stage bladder cancer, the role of radionuclide treatments has not been investigated yet. But in case a metabolic pathway can be viualised by a diagnostic radiopharmaceutical, then radiolabeled lesions can also be cured by the theranostic pair. Although F-18-FDG is a very good agent for detecting metastatic disease in bladder cancer, it cannot be used for theranostic purposes. Other routes are thus investigated for this aim.
Fibroblast activation protein (FAP) is highly expressed in the stroma of several tumor entities. Especially breast, colon, and pancreatic carcinomas are characterized by a strong desmoplastic reaction, which means that 90% of the gross tumor mass can consist of stromal but not tumor cells. Fibroblasts are present ubiquitously in the whole body and show very low or no FAP expression. In contrast, cancer-associated fibroblasts are specifically characterized by the expression of FAP (5).
Thus, cancer-associated fibroblasts differ from normal fibroblasts by providing FAP as a target with a relatively high tumor-specific expression, and FAP inhibitors (FAPIs) have already been developed as cancer drugs (6,7). Based on a quinoline-based FAP-specific inhibitor (6), a new class of radiopharmaceuticals was designed and found preclinically highly promising as molecular targeting imaging probes, and it is hoped that they also will be therapeutically useful (8,9).
First-in-human cases demonstrated high-contrast tumor imaging in various cancers, including bladder cancer (8-11). Thus, it has also been recognized as a promising target for therapy. To date, there are no studies available investigating FAPI targeted radionuclide therapy in bladder cancer.
The major aim of this study is investigating the safety and efficacy of Lu-177 FAP-2286 in advanced stage urothelial bladder cancer. The study is planned as a pilot study in a relatively small group of patients.
For non-standardised therapies, radionuclide therapies are adviced to be given with a dosimetric approach. In personalized therapies, dosimetry allows improved safety and efficacy, easier monitorisation of therapy, accurate measurement of radiation doses and thus minimizing adverse event rates while maximizing the therapeutic benefit in the targeted areas. So the secondary aim of this study is to make a dosimetric study, including the investigation of physiological distribution and pharmacokinetics-pharmacodynamics of this novel radiopharmaceutical.
Proving safety and efficacy in this pilot study will lead to open a window for its use in further clinical studies conducted in larger patient populations. Supported by further studies, a new therapeutic option will hopefully be developed for incurable bladder cancer.
