Long-Pentraxin 3 Derivative as a Small-Molecule FGF Trap for Cancer Therapy.
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.
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address: roberto.ronca@unibs.it.
Roberto
R
Ronca
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Arianna
A
Giacomini
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Emanuela
E
Di Salle
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Daniela
D
Coltrini
NMR Laboratory, Istituto per lo Studio delle Macromolecole, CNR, 20133 Milan, Italy.
Katiuscia
K
Pagano
NMR Laboratory, Istituto per lo Studio delle Macromolecole, CNR, 20133 Milan, Italy.
Laura
L
Ragona
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Sara
S
Matarazzo
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Sara
S
Rezzola
Chemistry for Technologies Laboratory and INSTM, School of Engineering, University of Brescia, 25123 Brescia, Italy.
Daniele
D
Maiolo
Istituto di Chimica del Riconoscimento Molecolare, CNR, 20133 Milan, Italy.
Rubben
R
Torrella
Istituto di Chimica del Riconoscimento Molecolare, CNR, 20133 Milan, Italy.
Elisabetta
E
Moroni
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia.
Roberta
R
Mazzieri
San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy; Vita Salute San Raffaele University, 20132 Milan, Italy.
Giulia
G
Escobar
Department of Pharmacy, University of Parma, 43121 Parma, Italy.
Marco
M
Mor
Istituto di Chimica del Riconoscimento Molecolare, CNR, 20133 Milan, Italy.
Giorgio
G
Colombo
Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address: marco.presta@unibs.it.
Marco
M
Presta
D000818:Animals; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000683:Serum Amyloid P-Component / Q000235:genetics* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000099153:Pentraxins
D002097:C-Reactive Protein; D005346:Fibroblast Growth Factors; D000683:Serum Amyloid P-Component; D054852:Small Molecule Libraries; D000099153:Pentraxins