Abstract
Fibroblast activation protein (FAP) is a protease biomarker that is selectively expressed on activated fibroblasts. Strongly FAP+ fibroblast are found in >90 of all tumors, in fibrotic tissue and in tissue remodeling. Researchers at UAntwerp earlier discovered UAMC1110: today the most potent and selective FAP inhibitor available. Radiolabeled derivatives of UAMC1110, called FAPIs, can be used as diagnostics or as therapeutics ('theranostics'). Nowadays, a steeply increasing number of FAPIs is being synthesized. This research proposal aims to bridge the current in vitro gap between FAPI design, synthesis and initial biochemical characterization on the one hand and the preclinical in vivo evaluation on the other. This will be realized by the development of FAPi-PLA, a test platform comprising: (1) a validated method for structure elucidation of FAP-FAPI complexes, (2) highly sensitive biosensor-based FAP-FAPI-binding assays for kinetic analyses of FAP-FAPI interactions and (3) a relevant cell-based assay to predict the FAPI-target residence time in a biological context. The project aims to obtain data for three existing FAPIs as reference compounds and at least two new FAPIs that are in the pipeline. To accelerate the development of FAPIs, there is an urgent need for such an efficient centralized platform. Within this project, we will develop the technology needed to create 'FAPi-PLA', a complete and modular in vitro FAPI test platform to accelerate FAPI development.
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