Long-term efficacy and downstream mechanism of anti-annexinA2 monoclonal antibody (anti-ANX A2 mAb) in a pre-clinical model of aggressive human breast cancer

Abstract

There is considerable direct evidence that calcium binding protein ANX A2 is a potential target for treating aggressive breast cancer. The most compelling data are based on the finding of ANX A2 overexpression in aggressive triple negative human breast cancer (TNBC) cell lines and in human breast cancer tissues. Previously, we and others reported a unique role of ANX A2 in cancer invasion, including breast cancer. Moreover, we demonstrated that anti-ANX A2 mAb-mediated immunoneutralization of ANX A2 inhibited invasive human breast cancer growth in a xenograft model. We further evaluated the long-term effects of multiple treatments with anti-ANX A2 mAb and its mechanism of inhibition on human breast tumor growth. We now demonstrate that three treatments with anti-ANX A2 mAb led to significant inhibition of breast tumor growth in immunodeficient mice, and that the anti-tumor response was demonstrable from day 94. After treatment, we followed tumor growth for 172 days and demonstrated 67% inhibition of tumor growth without detectable adverse effects. Biochemical analysis demonstrated that anti-ANX A2 mAb treatment caused significant inhibition of conversion of tissue plasminogen activator (tPA) in the tumor microenvironment. This led to disruption of plasmin generation that consequently inhibited activation of MMP-9 and MMP-2. These results suggest that ANX A2 plays an important role in aggressive breast tumor growth by regulating proteolytic pathways in the tumor microenvironment. ANX A2 may represent a new target for the development of therapeutics for treatment of aggressive breast cancer.

Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers

“…Further evaluation showed that immunoneutralization of ANX A2 inhibited activation of inactive proteolytic enzymes (pro‐MMP‐2 and pro‐MMP‐9). Inactive enzymes accumulated in the tumor microenvironment . Accumulation of inactive enzymes are most likely due to the inhibition of plasmin.…”

“…These data suggest that ANX A2 regulates activation of proteolytic enzymes through plasmin generation. It is likely that active forms of MMP‐2,MMP‐9, and VEGF acts as feedback loop to accelerate ECM degradation, and neoangiogenesis leading to invasive and metastatic cancer (Fig. ).…”

Annexin A13 promotes tumor cell invasion in vitro and is associated with metastasis in human colorectal cancer

“…To uncover the potential molecular pathways underlying ANXA13-enhanced tumor cell invasion and migration, we determined whether the ANXA13 downstream protein MMP-9, which is known for its role in cancer metastasis and tumor cell migration and invasion [24, 25], is involved in the process. Interestingly, we found that MMP-9 expression by Gelatin zymographic analysis was upregulated by ANXA13 overexpression in SW620 and Rko cells, but downregulated in HCT 116 and HT29 cells (Figure 6A).…”

Relationship Between Circulating Tumor Cells and Tissue Plasminogen Activator in Patients with Early Breast Cancer

“…Overexpression of annexin II was correlated with poor response to neoadjuvant chemotherapy in breast cancer and is detected mostly in aggressive breast cancer subtypes (16,17). In mouse models, treatment with an antibody to annexin led to a significant inhibition of breast tumor growth and to an inhibition of conversion of tPA in the tumor microenvironment (18).…”