Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies

Abstract

Introduction Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. Methods A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15th of July 2022) to search for prospective trials on FAP TRT. Results In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD. Conclusion To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.

Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer

“…However, the sponsor ceased further exploration of the drug because of a change in priorities in the portfolio ( ClinicalTrials.gov, ID: NCT03386721 ). Nonetheless, several active trials test the use of FAP to direct imaging agents ( Chandekar et al, 2023 ) and radiotheranostics ( Privé et al, 2023 ) to the tumors with fibroblast-rich stroma.…”

Beyond Small Molecules: Antibodies and Peptides for Fibroblast Activation Protein Targeting Radiopharmaceuticals

“…Another antibody, S5, exhibited expression patterns similar to mAbF19 but had limited in vivo expression [ 92 ]. It became evident that the fibroblasts surrounding tumor cells offer effective targets for cancer immunolocalization or immunotherapy, owing to their recognition by mAbF19 [ 129 , 130 , 131 ].…”

177Lu-FAP-2286 Therapy in a Case of Recurrent Bladder Cancer With Multiple Metastatic Lesions

“…3-6 177 Lu-FAP-2286 promises to be an effective radiopharmaceutical for long retention and high uptake with acceptable adverse effects. 3,7,8 Previous study has reported the absorbed doses of 177 Lu-FAP-2286 for the whole body. 8 Our case shows the efficacy of 177 Lu-FAP-2286 for the treatment of metastatic bladder cancer, but there are still further studies needed.…”

“…FAP-targeting radionuclide therapy has been applied in refractory tumors of various types 3–6 . 177 Lu-FAP-2286 promises to be an effective radiopharmaceutical for long retention and high uptake with acceptable adverse effects 3,7,8 . Previous study has reported the absorbed doses of 177 Lu-FAP-2286 for the whole body 8 .…”