An extracellular FGF trap derived from long pentraxin 3 (PTX3) inhibits FGF-driven tumorigenesis.
Major finding: An extracellular FGF trap derived from long pentraxin 3 (PTX3) inhibits FGF-driven tumorigenesis.
Approach: Pharmacophore modeling of a minimal FGF-binding peptide identified a PTX3-derived small molecule.
Impact: Small-molecule FGF traps may reduce tumor growth, angiogenesis, and metastasis of FGF-driven tumors.
During tumor growth and progression, FGFs and FGFRs are activated through overexpression, gene amplification, or mutations and promote tumor growth and escape from antiangiogenic therapy; however, development of effective inhibitors of the FGF/FGFR system has been challenging. The soluble pattern recognition receptor long pentraxin 3 (PTX3) binds multiple FGFs and antagonizes FGF-mediated angiogenesis, thus acting as a natural FGF trap. To further assess the therapeutic potential of PTX3 as an FGF ligand trap, Ronca, Giacomini, and colleagues generated transgenic mice specifically overexpressing human PTX3 in endothelial cells under the control of the Tie2 promoter. PTX3 overexpression impaired FGFR1 activation in vivo in response to FGF2 and inhibited the growth, vascularization, and metastasis of different FGF-dependent tumors in various heterotopic, orthotopic, and autochthonous murine tumor models, but had no effect on FGF-independent tumorigenesis. Consistent with this finding, mice deficient in Ptx3 exhibited increased FGF2-mediated angiogenesis, tumor growth, and metastasis in a syngeneic tumor model. In an effort to develop a synthetic compound that mimics the FGF trap activity of PTX3, the minimal amino acid sequence sufficient to disrupt FGF2/FGFR1 and FGF2/PTX3 interactions was used in pharmacophore modeling to screen small-molecule libraries. This approach identified NSC12 as a PTX3-derived multi-FGF trap; treatment with NSC12 blocked FGF-mediated angiogenesis and suppressed the proliferation of FGFR-dependent murine and human tumor cell lines. Furthermore, NSC12 disrupted FGF–FGFR signaling in vivo, resulting in reduced tumor growth and metastasis of FGF-dependent tumors when administered either intraperitoneally or orally. These data support further development of small-molecule FGF traps as a therapeutic strategy to inhibit FGF–FGFR signaling in cancer.