title: 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.
authors.affiliation: Research Service, Veterans Affairs Medical Center, Washington, DC 20422, USA; Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, USA. Electronic address: Mahesh.Sharma@va.gov.
authors.forename: Mahesh C
authors.initials: MC
authors.lastname: Sharma
authors.affiliation: Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Tuszynski
authors.affiliation: Research Service, Veterans Affairs Medical Center, Washington, DC 20422, USA; Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, USA; Department of Medicine, George Washington University, Washington, DC, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Blackman
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Breast cancer; Neoangiogenesis; Plasmin; Tumor microenvironment