In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation.

backgroundFibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in selecting promising FAP-targeted radiopharmaceuticals and for obtaining an increased understanding of factors essential for FAP-TRT improvement. FAP is mainly expressed by cancer-associated fibroblasts in the tumor stroma and less on cancer cells themselves. Therefore, other (complex) factors impact FAP-TRT efficacy compared to currently clinically applied TRT strategies. For accurate evaluation of these aspects, selection of a representative preclinical model is important. Currently mainly human cancer cell lines transduced to (over)express FAP are applied, lacking clinical representation. It is unclear how these and more physiological FAP-expressing models compare to each other, and whether/how the model influences the study outcome. We aimed to address this by comparing FAP tracer behavior in FAP-transduced HT1080-huFAP and HEK293-huFAP cells, and endogenous FAP-expressing U-87 MG cancer cells and PS-1 pancreatic stellate cells. [

resultsAlthough FAP expression was highest in HEK293-huFAP cells and cell line derived xenografts, this did not result in the highest tracer uptake. [

conclusionsThe interaction between FAP and FAP-targeted tracers differs between models, indicating the need for appropriate model selection and that comparing results across studies using different models is difficult.