title: A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.
abstract: Secreted frizzled-related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer and stimulates angiogenesis via activation of the calcineurin/NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of β-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling and to evaluate whether SFRP2 is a viable therapeutic target. The antiangiogenic and antitumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, tube formation assays, and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor-bearing and nontumor-bearing mice. SFRP2 mAb was shown to induce antitumor and antiangiogenic effects in vitro and inhibit activation of β-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared with control (P = 0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (P = 0.03) compared with control, whereas bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of β-catenin and NFATc3 in endothelial and tumor cells and is a novel therapeutic approach for inhibiting angiosarcoma and triple-negative breast cancer.
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Fontenot
authors.forename: Emma
authors.initials: E
authors.lastname: Rossi
authors.forename: Russell
authors.initials: R
authors.lastname: Mumper
authors.forename: Stephanie
authors.initials: S
authors.lastname: Snyder
authors.forename: Sharareh
authors.initials: S
authors.lastname: Siamakpour-Reihani
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.forename: Eleanor
authors.initials: E
authors.lastname: Hilliard
authors.forename: Bradley
authors.initials: B
authors.lastname: Bone
authors.forename: David
authors.initials: D
authors.lastname: Ketelsen
authors.forename: Charlene
authors.initials: C
authors.lastname: Santos
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Nancy
authors.initials: N
authors.lastname: Klauber-DeMore
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006394:Hemangiosarcoma / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008565:Membrane Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins