A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth

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

Research output: Research - peer-reviewArticle

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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 triplenegative 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.

LanguageEnglish (US)
Pages685-695
Number of pages11
JournalMolecular Cancer Therapeutics
Volume12
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Monoclonal Antibodies
Growth
Neoplasms
FRZB protein
NFATC Transcription Factors
beta Catenin
Tumor Burden
Endothelial Cells
Breast Neoplasms
Hemangiosarcoma
Pharmacokinetics
Therapeutics
Angiosarcoma of the breast
In Vitro Techniques
Triple Negative Breast Neoplasms
Calcineurin
Heterografts
Nude Mice
Allografts
Western Blotting

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fontenot, E., Rossi, E., Mumper, R., Snyder, S., Siamakpour-Reihani, S., Ma, P., ... Klauber-DeMore, N. (2013). A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth. Molecular Cancer Therapeutics, 12(5), 685-695. DOI: 10.1158/1535-7163.MCT-12-1066

A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth. / Fontenot, Emily; Rossi, Emma; Mumper, Russell; Snyder, Stephanie; Siamakpour-Reihani, Sharareh; Ma, Ping; Hilliard, Eleanor; Bone, Bradley; Ketelsen, David; Santos, Charlene; Patterson, Cam; Klauber-DeMore, Nancy.

In: Molecular Cancer Therapeutics, Vol. 12, No. 5, 01.05.2013, p. 685-695.

Research output: Research - peer-reviewArticle

Fontenot, E, Rossi, E, Mumper, R, Snyder, S, Siamakpour-Reihani, S, Ma, P, Hilliard, E, Bone, B, Ketelsen, D, Santos, C, Patterson, C & Klauber-DeMore, N 2013, 'A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth' Molecular Cancer Therapeutics, vol 12, no. 5, pp. 685-695. DOI: 10.1158/1535-7163.MCT-12-1066
Fontenot E, Rossi E, Mumper R, Snyder S, Siamakpour-Reihani S, Ma P et al. A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth. Molecular Cancer Therapeutics. 2013 May 1;12(5):685-695. Available from, DOI: 10.1158/1535-7163.MCT-12-1066
Fontenot, Emily ; Rossi, Emma ; Mumper, Russell ; Snyder, Stephanie ; Siamakpour-Reihani, Sharareh ; Ma, Ping ; Hilliard, Eleanor ; Bone, Bradley ; Ketelsen, David ; Santos, Charlene ; Patterson, Cam ; Klauber-DeMore, Nancy. / A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 5. pp. 685-695
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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 triplenegative 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.",
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