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

Roberto Ronca; Arianna Giacomini; Emanuela Di Salle; Daniela Coltrini; Katiuscia Pagano; Laura Ragona; Sara Matarazzo; Sara Rezzola; Daniele Maiolo; Rubben Torrella; Elisabetta Moroni; Roberta Mazzieri; Giulia Escobar; Marco Mor; Giorgio Colombo; Marco Presta

doi:10.1016/j.ccell.2015.07.002

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.

Authors

Roberto Ronca¹, Arianna Giacomini², Emanuela Di Salle², Daniela Coltrini², Katiuscia Pagano³, Laura Ragona³, Sara Matarazzo², Sara Rezzola², Daniele Maiolo⁴, Rubben Torrella⁵, Elisabetta Moroni⁵, Roberta Mazzieri⁶, Giulia Escobar⁷, Marco Mor⁸, Giorgio Colombo⁵, Marco Presta⁹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
C-Reactive Protein / genetics*
C-Reactive Protein / metabolism
Cell Cycle / drug effects
Cell Cycle / genetics
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Cells, Cultured
Female
Fibroblast Growth Factors / genetics*
Fibroblast Growth Factors / metabolism
Fibroblast Growth Factors / pharmacology
Gene Expression Regulation, Neoplastic*
Humans
Kaplan-Meier Estimate
Male
Mice, Inbred C57BL
Mice, Nude
Mice, Transgenic
Molecular Structure
Neoplasms / genetics*
Neoplasms / metabolism
Neoplasms / therapy
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Serum Amyloid P-Component / genetics*
Serum Amyloid P-Component / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays / methods

Substances

Serum Amyloid P-Component
Small Molecule Libraries
PTX3 protein
Fibroblast Growth Factors
C-Reactive Protein