What question did this study set out to answer?

This study aims to evaluate the combined antitumor effects of [177Lu]Lu-FAPI-2286 and pazopanib in a sarcoma model.

March 7, 2026Open Access

Combined antitumor activity of 177LuLu-FAPI-2286 and pazopanib in a sarcoma model: a preclinical theranostic study targeting fibroblast activation protein

Key Points

This study aims to evaluate the combined antitumor effects of [177Lu]Lu-FAPI-2286 and pazopanib in a sarcoma model.
Utilized patient-derived xenograft sarcoma mouse model.
Assessed therapeutic efficacy through [18F]F-FAPI-74 PET imaging and pathological analyses.
Conducted microPET and microSPECT imaging to evaluate tracer uptake.
Performed immunohistochemical analysis to assess tumor responses.
Combination therapy resulted in approximately six-fold tumor growth suppression compared to control.
Markedly decreased tracer uptake observed in combination group (SUVmean = 0.68 ± 0.20).
Reduced FAP expression (− 38% versus control) and decreased Ki-67 proliferation index (− 70%) in treated tumors.
Elevated cleaved caspase-3 levels indicated enhanced apoptosis.

Abstract

Sarcomas comprise a heterogeneous group of aggressive mesenchymal malignancies with limited therapeutic options and poor prognosis, underscoring the need for novel treatment strategies. Fibroblast activation protein (FAP), which is highly expressed on sarcoma-associated fibroblasts within the tumor microenvironment, has emerged as a promising target for precision radioligand therapy. To evaluate this approach, we employed a patient-derived xenograft (PDX) sarcoma mouse model to investigate 177LuLu-FAPI-2286 radioligand therapy. Therapeutic efficacy was assessed longitudinally in vivo using 18FF-FAPI-74 PET imaging and subsequently corroborated by pathological analyses. The radiosynthesis of both 18FF-FAPI-74 (n = 8) and 177LuLu-FAPI-2286 (n = 3) achieved high radiochemical purity (> 95%), confirming their suitability for subsequent applications. Both tracers showed similar biodistribution patterns with predominant renal clearance. MicroPET imaging demonstrated clear 18FF-FAPI-74 uptake in PDX sarcomas (SUVmean = 0.60 ± 0.12), and microSPECT imaging revealed detectable 177LuLu-FAPI-2286 tumor uptake (SUVmean = 0.20 ± 0.18). In the in vivo evaluation of therapeutic efficacy, the combination therapy (177LuLu-FAPI-2286 + pazopanib) demonstrated the most pronounced antitumor effect, suppressing tumor growth by approximately six-fold compared with the control group, without inducing body weight loss or overt toxicity. Longitudinal 18FF-FAPI-74 PET imaging revealed markedly decreased tracer uptake in the combination group (SUVmean = 0.68 ± 0.20) compared with the control (SUVmean = 1.42 ± 0.47) and pazopanib monotherapy (SUVmean = 1.22 ± 0.11) groups. Immunohistochemical analysis confirmed reduced FAP expression (− 38% versus control), decreased Ki-67 proliferation index (− 70%), and elevated cleaved caspase-3 levels (~ 2-fold increase) in radioligand-treated tumors, indicating enhanced apoptosis and an improved therapeutic response. 177LuLu-FAPI-2286 demonstrated significant therapeutic potential against sarcoma in our preclinical model, with an apparent enhancement when combined with pazopanib. Additionally, 18FF-FAPI-74 PET imaging proved valuable as a non-invasive radiotracer for treatment monitoring. These findings provide strong preclinical evidence supporting the advancement of FAP-targeted radioligand therapy in combination with pazopanib into clinical trials.

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