LAUSR

The legendary surgeon-scientist Judah Folkman contributed a wealth of discoveries on the fundamental role of angiogenesis in cancer and other diseases. This line of investigation led to more than 50 angiogenesis inhibitors being investigated in clinical trials and at least 10 that are currently approved by the US FDA. Angiogenesis inhibitors work via a variety of mechanisms of action. Some specifically bind to (1) vascular endothelial growth factor (VEGF) or its receptor; (2) other growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF); or (3) receptors or proteins on endothelial cells, blocking the growth of blood vessels. Angiogenesis inhibitors remain an attractive topic for preclinical development for cancer therapy. Secreted frizzled-related protein 2 (SFRP2) is a modulator of Wnt signaling that is expressed in the vascular endothelium of the majority of solid tumors. Courtwright et al. reported that SFRP2 mediates angiogenesis by demonstrating that tacrolimus inhibition of SFRP2 decreased vascular tube formation in vitro and reduced the growth of angiosarcoma xenografts in vivo. Garcia et al. build upon this work in the article entitled ‘‘Development of a novel humanized monoclonal antibody to secreted frizzled-related protein-2 that inhibits metaplastic breast cancer and angiosarcoma growth in vivo’’. This study focuses attention to SFRP2 inhibition in angiosarcomas and triple-negative breast cancer, two aggressive malignancies where there exists an unmet need for targeted therapies directed at tumor biology. Targeted therapy efficacy is improved when biomarkers can be found that help identify a responding patient population. It is encouraging that SFRP2 does appear to be strongly expressed in around 70% of breast cancers as well as many other types of cancers based on a query of The Human Protein Atlas (www.proteinatlas.org). The authors have found that SFRP2 is broadly expressed across a variety of solid malignancies, both epithelial and mesenchymal in origin. Specifically, high SFRP2 expression is seen in 85% of triple-negative breast cancers and 100% of angiosarcomas. Other investigators have also shown that the family of SFRPs appears to play an important role in osteosarcoma. Importantly, SFRP2 and its related isoforms are involved in the Wnt pathway, which plays a critical role for many other sarcoma subtypes (e.g. desmoid tumors, synovial sarcoma), which suggests potentially even more relevance for this particular group of malignancies. The authors elegantly demonstrated that their humanized monoclonal antibody against SFRP2 reduced tumor growth and increased apoptosis of SVR angiosarcomas and Hs578T triple-negative breast cancers in vivo. There is definitely a need to demonstrate preclinical efficacy in mice prior to human clinical trials, but the immunodeficient mouse model and the lack of immune response when tested in vitro with healthy human blood argues against the mechanism of action being related to the host immune response. This could be further studied using immunocompetent syngeneic mouse models such as 4T1 in BALB/ c mice to model triple-negative breast cancer. Alternatively, genetically engineered mouse models such as FVBSociety of Surgical Oncology 2019