title: Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.
abstract: The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039-mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or β-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.
authors.affiliation: Five Prime Therapeutics Inc., South San Francisco, CA 94080-7047, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Harding
authors.forename: Li
authors.initials: L
authors.lastname: Long
authors.forename: Servando
authors.initials: S
authors.lastname: Palencia
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Ali
authors.initials: A
authors.lastname: Sadra
authors.forename: Kevin
authors.initials: K
authors.lastname: Hestir
authors.forename: Namrata
authors.initials: N
authors.lastname: Patil
authors.forename: Anita
authors.initials: A
authors.lastname: Levin
authors.forename: Amy W
authors.initials: AW
authors.lastname: Hsu
authors.forename: Deborah
authors.initials: D
authors.lastname: Charych
authors.forename: Thomas
authors.initials: T
authors.lastname: Brennan
authors.forename: James
authors.initials: J
authors.lastname: Zanghi
authors.forename: Robert
authors.initials: R
authors.lastname: Halenbeck
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Marshall
authors.forename: Minmin
authors.initials: M
authors.lastname: Qin
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Doberstein
authors.forename: Diane
authors.initials: D
authors.lastname: Hollenbaugh
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kavanaugh
authors.forename: Lewis T
authors.initials: LT
authors.lastname: Williams
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Baker
mesh_terms: D002118:Calcium / Q000097:blood; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000627:therapeutic use*; D010710:Phosphates / Q000097:blood; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins
chemical_list: C000717427:FGF23 protein, human; D007074:Immunoglobulin G; D015514:Oncogene Proteins, Fusion; D010710:Phosphates; D011993:Recombinant Fusion Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C559041:FP-1039; D051496:Receptor, Fibroblast Growth Factor, Type 1; D002118:Calcium