Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions. Dysregulated FGF signaling has been implicated in the pathogenesis of human cancers. FGF receptor 2 (FGFR2) is a member of highly conserved receptor tyrosine kinases (RTKs), namely, FGF receptors 1–4 (FGFR1–4), which mediate the pleiotropic effects of FGFs. Aberrant activation of FGFR2 signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. Many studies have reported that activating mutations of FGFR2 exist in multiple cancer types, like gastric and breast cancers. Furthermore, the FGFR2 gene is amplified in a subset of gastric and breast cancers and associated with poor prognosis. Recently, FGFR2 has emerged as a candidate cancer therapeutic target. Several tyrosine kinase inhibitors (TKIs) against FGFR2 signaling have been evaluated for their anti-tumor activity on cancer cell proliferation and survival. However, many of these TKIs have multiple targets, which makes them less potent against FGFR2, and it is uncertain if this will be a disadvantage in clinical development. To minimize the side effects of targeting FGFR2, therapeutic antibodies may have substantial benefits, as they can be used to treat cancer cells that are reliant on a particular FGFR2 and therefore reduce the potential toxicity. Taken together, cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. In this year project, several anti-FGFR2 single chain variable fragment (scFv) candidates with different binding specificities have been isolated in the previous studies by phage display technology. One scFv F2pS3 can block the active site of FGFR2 to prevent ligand FGF7 access and has the ability to inhibit cell growth of gastric cancer. These results illustrate the value of the follow-up study. In the future, we will continue to explore the ability of these candidate antibodies against gastric cancer cells. These antibodies may have comprehensive inhibition effects against FGFRs and are worthy for further studies. Once these antibodies develop into antibody drugs, they will be able to develop more efficient target therapeutics against gastric and other FGFR-associated cancers.
|Effective start/end date||4/1/15 → 7/31/16|
- Fibroblast growth factor
- FGF receptor 2
- single chain variable fragment
- phage display technology