FP-1039 (FGFR1:Fc), a soluble FGFR1 receptor antagonist, inhibits tumor growth and angiogenesis

TLDR: Data indicate the potential for FP-1039 to be a selective and potent anti-cancer drug for the treatment of certain cancers in which the FGF-FGFR pathway plays an important role in supporting the tumor/host interaction, while possibly avoiding some of the dose limiting toxicities identified previously with oral tyrosine kinase inhibitors.

Abstract: B55 FP-1039 is a soluble fusion protein consisting of the extracellular domain of human fibroblast growth factor receptor 1c (FGFR1) linked to the Fc portion of human IgG1. In these studies, we investigate the anti-tumor effect of FP-1039 in cell line-derived and primary human tumor-derived xenograft models, and quantify the anti-angiogenic effect on both fibroblast growth factor- (FGF) and vascular endothelial growth factor- (VEGF) induced angiogenesis. Most of the known 23 human FGF ligands bind to more than one FGF receptor subtype; therefore, a drug that specifically targets the FGFR1 receptor, such as an anti-FGFR1 monoclonal antibody, will not prevent binding of FGFR1 ligands to other FGF receptor subtypes. Thus, FP-1039 was engineered to prevent all FGFR1 ligands from binding to any of the four FGF receptors.
 The FGF-FGFR signaling pathway is implicated in the pathogenesis of many cancers. The gene encoding FGFR1 is located within a region on chromosome 8 (8p11-12) that is amplified within specific subsets of breast cancer patients for whom presence of the amplicon strongly predicts shorter metastasis-free survival. FGFR1 ligands, such as FGF-2, possess not only mitogenic activity, but also have potent angiogenic activities that promote tumor progression. This dual cancer promoting mechanism of tumor growth stimulation and angiogenesis makes FGF-FGFR signaling an attractive target for therapeutic intervention.
 FP-1039 inhibits the growth of several human cell-lined derived tumors in xenograft models, including Caki-1, A549 and MCF-7. It also inhibits tumor growth in specific human primary tumor derived xenografts which are well characterized with respect to key cell surface markers associated with the FGF-FGFR pathway. Such models may greatly facilitate our ability to identify tumor markers associated with response specificity to FP-1039, and may facilitate patient selection criteria for clinical trials.
 To assess the anti-angiogenic activity of FP-1039 in vivo we employed a model in which neovascularization is driven by the presence of human angiogenic factors in a matrigel plug that is implanted subcutaneously into mice. In a dose dependent fashion, FP-1039 completely inhibited the neovascularization induced by either FGF-2 or VEGF alone, and that induced by a combination of FGF-2 plus VEGF. Endothelial staining of tumor sections from a Caki-1 xenograft in which FP-1039 treatment resulted in a dose dependent inhibition of tumor growth also revealed qualitative differences in the tumor vasculature including a marked reduction in vessel density compared to animals treated with control.
 The preclinical studies performed thus far demonstrate the anti-tumor effect of FP-1039 in both cell line-derived and primary human tumor-derived xenograft models, and the potent inhibition of both FGF and VEGF-induced angiogenesis. These data indicate the potential for FP-1039 to be a selective and potent anti-cancer drug for the treatment of certain cancers in which the FGF-FGFR pathway plays an important role in supporting the tumor/host interaction, while possibly avoiding some of the dose limiting toxicities identified previously with oral tyrosine kinase inhibitors that block multiple tyrosine kinases.