Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy

• DOI: 10.1016/j.ccell.2015.08.007
• Publication Date: 2015-09-14T15:45:13Z
• Authors: Roberto Ronca; Arianna Giacomini; Emanuela Di Salle; Daniela Coltrini; Katiuscia Pagano; Laura Ragona; Sara Matarazzo; Sara Rezzola; Daniele Maiolo; Rubben Torella; Elisabetta Moroni; Roberta Mazzieri; Giulia Escobar; Marco Mor; Giorgio Colombo; Marco Presta
• Keywords: Male; 0301 basic medicine; pentraxin, FGF, FGFR, cancer, cancer therapy, angiogenesis; x; Cancer Research; FGF2; pentraxin; Cell Survival; Blotting, Western; 610; Mice, Nude; Mice, Transgenic; Kaplan-Meier Estimate; TUMOR ANGIOGENESIS; 1307 Cell Biology; ACTIVATION; 03 medical and health sciences; INFLAMMATION; ANTAGONISTS; antineoplastic molecule; RECOGNITION RECEPTOR PTX3; Cell Line, Tumor; Neoplasms; structural biology; Animals; Humans; 1306 Cancer Research; Cells, Cultured; Molecular Structure; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; Cell Cycle; INHIBITOR; FGF TRAP; Cell Biology; NMR; PROSTATE-CANCER; PENTAPEPTIDE; 3. Good health; Fibroblast Growth Factors; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; C-Reactive Protein; ANTIBODY; Oncology; GROWTH; 2730 Oncology; Female

The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance, and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. Here we demonstrate that human PTX3 overexpression in transgenic mice driven by the Tie2 promoter inhibits tumor growth, angiogenesis, and metastasis in heterotopic, orthotopic, and autochthonous FGF-dependent tumor models. Using pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2, we identified a small-molecule chemical (NSC12) that acts as an extracellular FGF trap with significant implications in cancer therapy.