Abstract #1034

In general tumor associated macrophages confer a negative prognosis in patients with breast cancer. This is due in part to the fact that macrophages can promote angiogenesis and mediate the angiogenic switch in tumors. Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis as well as a macrophage chemotactic protein. Inhibition of VEGF is an attractive therapeutic strategy that has shown to be beneficial in combination with chemotherapy for some breast cancer patients. However, the mechanism by which inhibition of VEGF affects tumor growth appears to involve more than its effect on endothelial cells. We have previously shown that 2C3 (PGN-310), a mouse monoclonal antibody that prevents VEGF from binding to VEGF receptor 2, decreases tumor growth, angiogenesis, and macrophage infiltration into pancreatic tumors. In this study, we test a fully human version of 2C3, termed r84 (PGN-311), for its effect on established orthotopic MDA-MB-231 breast tumors in SCID mice. Orthotopic tumors were established by injecting one million MDA-MB-231 cells into the mammary fat pad of SCID mice. Therapy with saline (n=5), bevacizumab (n=8), 2C3 (n=5), or r84 (n=9) at 250 μg/ip injection twice weekly was initiated on day 26 post tumor cell injection (mean initial tumor volume = 150 mm3) and continued for approximately 3 weeks. Upon sacrifice, tumor weight was determined and the tumor and other organs were snap frozen or fixed in formalin and paraffin-embedded for histology. Anti-VEGF therapy inhibited growth of orthotopic breast tumors (on day 48, Mean ± SEM: control, 822 ± 160; bevacizumab, 344 ± 29; 2C3, 309 ± 69; r84, 368 ± 38 mm3;all p < 0.001 vs control). Furthermore, immunohistochemical analysis of tumors from control and anti-VEGF treated animals demonstrated that each anti-VEGF therapy reduced microvessel density and macrophage infiltration. Additionally, we also determined that inhibition of VEGF activity with 2C3 reduces VEGF-induced migration of MDA-MB-231 cells in vitro in a transwell assay. In summary, we demonstrate that r84 a unique fully human anti-VEGF antibody is effective in reducing tumor microvessel density, macrophage infiltration into tumors, and the growth of breast tumors implanted into SCID mice. These data suggest that inhibition of VEGF receptor 2 activity with an anti-VEGF monoclonal antibody is sufficient for effective blockade of the pro-tumorigenic activities of VEGF.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1034.

Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX