Abstract
Fibroblast activation protein (FAP) is an enzyme highly expressed on activated fibroblasts in tumors and fibrotic disease, with low or negligible expression in normal healthy tissues, making it an attractive biomarker for these diseases. FAPIs are small molecules designed to target FAP with high affinity and selectivity, often conjugated with a radionuclide for use as diagnostic or therapeutic tools in cancer treatment. As novel FAPIs are continually produced, robust methods for testing and selecting the most promising compounds are essential. This project aims to optimize two techniques for kinetic characterization of FAPIs. Given the limited knowledge of FAP behavior upon FAPI binding, we seek to gain structural insights into FAPI-binding behavior using cryo-EM on FAP-FAPI complexes. Additionally, while FAPIs are known to cause internalization upon binding, the fate of FAP during internalization remains unclear. We will study FAP internalization using techniques such as flow cytometry and live cell imaging. Furthermore, findings observed in vitro will be translated to in vivo models to assess their accuracy and relevance. A more profound understanding of these fundamental questions about FAP-FAPI interactions can contribute to the development of improved FAPIs in the future, which can pave the way for innovative therapies in cancer and fibrotic disease.
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