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

  • Cancer Cell. 2015 Aug 10;28(2):225-39. doi: 10.1016/j.ccell.2015.07.002.
Roberto Ronca  1 ,  Arianna Giacomini  2 ,  Emanuela Di Salle  2 ,  Daniela Coltrini  2 ,  Katiuscia Pagano  3 ,  Laura Ragona  3 ,  Sara Matarazzo  2 ,  Sara Rezzola  2 ,  Daniele Maiolo  4 ,  Rubben Torrella  5 ,  Elisabetta Moroni  5 ,  Roberta Mazzieri  6 ,  Giulia Escobar  7 ,  Marco Mor  8 ,  Giorgio Colombo  5 ,  Marco Presta  9
Affiliations
  • 1. Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address: [email protected].
  • 2. Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
  • 3. NMR Laboratory, Istituto per lo Studio delle Macromolecole, CNR, 20133 Milan, Italy.
  • 4. Chemistry for Technologies Laboratory and INSTM, School of Engineering, University of Brescia, 25123 Brescia, Italy.
  • 5. Istituto di Chimica del Riconoscimento Molecolare, CNR, 20133 Milan, Italy.
  • 6. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia.
  • 7. San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
  • 8. Department of Pharmacy, University of Parma, 43121 Parma, Italy.
  • 9. Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address: [email protected].
PMID: 26267536 DOI: 10.1016/j.ccell.2015.07.002
Abstract

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.