Dataset Information

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 15^th 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.

SUBMITTER: Prive BM

PROVIDER: S-EPMC10199876 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Privé Bastiaan M BM Boussihmad Mohamed A MA Timmermans Bart B van Gemert Willemijn A WA Peters Steffie M B SMB Derks Yvonne H W YHW van Lith Sanne A M SAM Mehra Niven N Nagarajah James J Heskamp Sandra S Westdorp Harm H

European journal of nuclear medicine and molecular imaging 20230223 7

<h4>Introduction</h4>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 ...[more]

PMID: 36813980

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Project description:PurposeA series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68-labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics.MethodsThe precursor LuFL (20) and [natLu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [177Lu]Lu-LuFL ([177Lu]21) and [177Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy.ResultsLuFL (20) and [natLu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC50: 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC50: 6.69 ± 0.88 nM). In vitro cellular studies showed that 18F-/177Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [18F]/[177Lu]21 revealed higher tumor uptake and longer tumor retention than those of [68 Ga]/[177Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [177Lu]21 group, than for the control group and the [177Lu]Lu-FAPI-04 group.ConclusionThe novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with 18F- and 177Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy.

Dataset Information

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

Introduction

Results

Conclusion

Publications

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

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