BACKGROUND:Prostate cancer (PCa) is the second leading cause of death in men and is highly prone to metastasis. This study aims to develop the novel immuno-PET/CT tracer targeting trophoblast cell surface antigen 2 (Trop2), a transmembrane protein overexpressed in aggressive prostate malignancies, and to investigate its diagnostic value in preclinical studies as well as its potential utility in detecting metastases in PCa patients.
METHODS:Integrated analysis of TCGA, GEO, and HPA datasets revealed Trop2 overexpression in prostate adenocarcinoma. By labeling two Trop2-targeted nanobodies (His-tagged T4 and His-tag-free RT4) with 68Ga and 18F, we synthesized three radiotracers, [68Ga]Ga-NOTA-T4, [18F]AlF-RESCA-T4, and [18F]AlF-RESCA-RT4. Preclinical validation included cellular assays and xenograft studies for 68Ga/18F-T4 variants, followed by a first-in-human trial evaluating [18F]AlF-RESCA-RT4 in ten treatment-naïve PCa patients.
RESULTS:Bioinformatics analysis demonstrated Trop2 as a promising target for PCa diagnosis and treatment. In preclinical studies, both [68Ga]Ga-NOTA-T4 and [18F]AlF-RESCA-T4 illustrated high affinity to Trop2, specific tumor uptake (4.33 ± 0.38 %ID/g and 5.50 ± 0.69 %ID/g at 60 min, respectively) in Trop2-positive xenograft mouse models with minimal background distribution. In the translational study, [18F]AlF-RESCA-RT4 outperformed standard [18F]-FDG imaging in metastatic prostate cancer patients, detecting 62.4% more lymph node metastases (SUVmax 21.58 ± 13.12 vs. 4.80 ± 1.77) and 69.4% more bone lesions (SUVmax 7.83 ± 4.32 vs. 4.72 ± 1.22). No adverse events were observed.
CONCLUSIONS:This work successfully establishes that Trop2 is a new biomarker for PCa, and Trop2 immuno-PET/CT imaging can detect PCa lymph node and osseous metastases. The superior tumor-to-background contrast and clinical safety of [18F]AlF-RESCA-RT4 support its translational potential to guide Trop2-targeted therapies and enhance personalized treatment strategies.
TRIAL REGISTRATION:NCT06851663. Retrospectively registered 02/24/2025.