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Antiangiogenic Monoclonal Antibody Slows Tumor Growth in Breast Cancer and Angiosarcoma Models

By BiotechDaily International staff writers
Posted on 29 Apr 2013
A monoclonal antibody specific for a protein linked to the angiogenesis required for tumor growth was shown to have potent antitumor and antiangiogenic properties both in vitro and in mouse xenograft models.

Investigators at the University of North Carolina (Chapel Hill, USA) had found previously that secreted frizzled-related protein 2 (SFRP2) was overexpressed in human angiosarcoma and breast cancer and stimulated angiogenesis via activation of the calcineurin/NFATc3 pathway. Subsequently, SFRP2 was found in a variety of other human cancers, including prostate, lung, pancreas, ovarian, colon, and kidney.

In the current study, the investigators assessed the effects of a novel monoclonal antibody (mAb) that blocked SFRP2 expression. They examined the effect of this antagonism on tumor growth and Wnt-signaling and evaluated whether SFRP2 would be a viable therapeutic target.

The antiangiogenic and antitumor properties of the SFRP2 mAb were determined using in vitro proliferation, migration, and tube formation assays and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with the SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor bearing and control mice.

Results published in the April 19, 2013, online edition of the journal Molecular Cancer Therapeutics revealed that the SFRP2 mAb induced antitumor and antiangiogenic effects in vitro and inhibited activation of beta-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. An increase in beta-catenin production has been noted in those people with basal cell carcinoma and leads to the increase in proliferation of related tumors.

Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% while treatment of MDA-MB-231 breast carcinoma xenografts decreased tumor volume by 52%. Pharmacokinetic studies showed that the antibody was long circulating in the blood and preferentially accumulated in SFRP2-positive tumors.

“We previously microdissected blood vessels from malignant human breast cancers and compared gene expression to blood vessels microdissected from normal tissue. We found a number of genes that were highly over-expressed in the malignant blood vessels compared to normal. One of those genes was SFRP2,” said senior author Dr. Nancy Klauber-DeMore, professor of surgery at the University of North Carolina.

“We showed in this paper that targeting SFRP2 with a monoclonal antibody in preclinical models inhibits tumor growth. This demonstrates that SFRP2 is a therapeutic target for cancer,” said Dr. Klauber-DeMore. “Demonstrating that a monoclonal antibody to SFRP2 inhibits tumor growth in preclinical models opens up a new potential for drug development. This treatment is not presently available for human studies, but our efforts are focused on obtaining funding for further drug development that would lead to a clinical trial.”

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University of North Carolina



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