Diagnosis and therapy of aggressive breast cancers by targeting urokinase receptor

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S68-S68
• Main Authors: Harel, E, Liang, S, Brain, S, Gartner, Z, Van't Veer, L, Craik, C
• Format: Article
• Language: English
• Subjects: Animal models; Antibodies; Biotechnology; Breast cancer; Deoxyribonucleic acid; Diagnostic systems; DNA; Drug therapy; Epidermal growth factor; Estrogens; Glycoproteins; Hematology, Oncology and Palliative Medicine; Integrins; Medical diagnosis; Metastases; Molecular chains; Overexpression; Phenotypes; Progesterone; Protein interaction; Proteins; Proteolysis; U-Plasminogen activator; Urokinase
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32791-5

Background: Triple negative Breast Cancer (TNBC) is a highly aggressive BC subtype, with an increased likelihood of distant recurrence and of death compared with other types of BC. Patients diagnosed with TNBC lack the estrogen and progesterone receptor, the human epidermal growth factor 2 and do not respond well to current therapies. Targeted therapies such as epidermal growth factor receptor inhibitors, showed variable response rates but no survival benefit. One hallmark of aggressive cancers is increased urokinase receptor (uPAR) expression. The over-expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) have been found to contribute to the aggressive phenotype in a number of cancers and is found uniformly in many metastases. uPAR ubiquitousness in TNBC makes it an attractive target for uPAR-directed therapies. It participates in many protein/protein interactions, which leads to pericellular proteolysis and signaling that is mediated by specific integrins. Therefore, inhibition of one or more of these interactions would progressively contribute to a reduction in aggressive behavior. Material and Methods: Six inhibitory anti-uPAR Antibodies (Abs) were identified. Two of those Abs, referred to as 2G10 and 3C6, obstruct protein-protein interactions between uPAR and uPA or beta 1 integrin, respectively. The Abs were tested in in vitro and in vivo TNBC models and showed diagnostic and therapeutic potential. In a mouse model of TNBC the Abs targeting two distinct subdomains of slowed or blocked tumor growth. Moreover, treatment of TNBC cell lines in vitro with a combination of 2G10 and 3C6 demonstrated synergy, suggesting that blocking multiple uPAR effector functions simultaneously may provide a dramatically enhanced response. Results: The anti uPAR Abs. have been assembled using a modular platform to give bi-specific Abs based on DNA linkers. The platform enables a library of heterofunctional molecules to be made with precise geometries, valencies, and rigidities. Basic linear construct combining 3C6 and 2G10, have been tested for uPAR recognition ability and therapeutic effect in vitro in TNBC cell lines. Conclusions: Our results indicate that at fixed total protein concentration, the scaffolded Abs outperform the unscaffolded Abs in blocking MDA-MD-231 cell invasion.