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: Emily Fontenot, Emma Rossi, Russell Mumper, Stephanie Snyder, Sharareh Siamakpour-Reihani, Ping Ma, Eleanor Hilliard, Bradley Bone, David Ketelsen, Charlene Santos, Cam Patterson, Nancy Klauber-DeMore
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 5 Pg. 685-95 (May 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23604067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Membrane Proteins
• SFRP2 protein, human

Topics

• Allografts
• Animals
• Antibodies, Monoclonal (immunology, pharmacokinetics, pharmacology)
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endothelial Cells (drug effects, metabolism)
• Female
• Hemangiosarcoma (metabolism, pathology)
• Heterografts
• Humans
• Membrane Proteins (antagonists & inhibitors, immunology)
• Mice
• Mice, Nude
• Neoplasms (metabolism, pathology)
• Wnt Signaling Pathway (drug effects)