The objective of the proposed research is to characterize monoclonal antibodies (mAbs) that bind and block the Fibroblast Growth Factor (FGF) Receptor 2 (FGFR2) for potential use in cancer therapy. The FGF family of growth factors is a large group of factors believed to play a role in the growth of many tumors, as well as in aspects of normal development. In particular, FGF2 (basic FGF) is a powerful stimulator of angiogenesis, the new blood vessel formation needed by tumors to grow, while FGF7 (Keratinocyte Growth Factor) potently stimulates epithelial cell proliferation. FGFR2 is a major cellular receptor for FGF1, FGF2, FGF7 and other FGFs, and mutation and/or overexpression of FGFR2 has been associated with gastric, pancreatic, breast, ovarian and uterine tumors, so FGFR2 is a logical target for therapy of these cancers. The Applicant has already generated a panel of anti-FGFR2 mAbs and in preliminary studies shown that one of them completely inhibits growth of a gastric tumor xenograft. In the proposed research plan, the anti-FGFR2 mAbs will be further characterized both in vitro and in vivo, with a view to choosing the best mAb for further development toward clinical trials. The ability of each mAb to bind the FGFR2IIIb and FGFR2IIIc isoforms of FGFR2 will first be determined by ELISA assays and flow cytometry, as these isoforms play different roles in cancer. Then the ability of the mAbs to block binding of FGF1, FGF2 and FGF7 to FGFR2 will be investigated, as an optimal mAb will block all ligand/receptor binding. Next, the extent to which selected mAbs can inhibit FGF-induced and ligand-independent proliferation of tumor cell lines will be determined. The ability of the mAbs to bind to FGFR2 having certain mutations associated with uterine and other cancers will also be determined. Finally, experiments will be conducted to investigate the capability of the most potent mAbs to block growth of human gastric tumor xenografts in mouse models. It is expected that in Phase II of this grant proposal, more extensive animal model and mechanism of action studies will be conducted, and the most effective anti-FGFR2 mAb will be converted into a humanized antibody suitable for clinical development.
Public Health Relevance: Despite recent scientific advances, cancer remains a major medical problem. The objective of the planned program is to select a monoclonal antibody that targets the receptor for a growth factor believed to be involved in many tumors. The antibody will have the potential to be an effective drug for various types of cancer including gastric, pancreatic, breast, ovarian and uterine.
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