The uPA-uPAR enzyme system is involved in many malignancies, including pancreatic cancer. However progress in therapeutic targeting have been slow. Now, antibody therapies show potential to enter the clinic, allowing researchers to investigate the potential of uPA targeted therapy for cancer.
What is the uPA Enzyme System?
- The urokinase plasminogen activator enzyme system (uPA-uPAR) comprises the serine protease uPA and plasminogen activator inhibitors 1 and 2. This system appears to drive cancer progression by enabling tumor cells to breakdown surrounding tissue (proteolysis), and hence invade other tissues and spread throughout the body. Therefore uPAR is not usually expressed uniformly within a tumor, usually being restricted to cells at the invasive edge.
- Recent data have shown that in addition to proteolysis, the uPA-uPAR system is also involved in cell signaling, proliferation and survival of tumor cells.
- uPA system is an attractive target because its expression is generally restricted to tumor tissue and is not usually expressed by cells outside of the tumor microenvironment. However, uPAR may be up-regulated on some cells during non-cancerous processes such as wound healing and response to infection.
- uPAR expression can be increased by hypoxia (low oxygen conditions).
- Tumors that express uPAR can be classified into two categories: (i) Those that express uPAR on both tumor and tumor-associated cells: pancreatic cancer, bladder cancer and renal cell carcinoma (ii) Those that do not express uPAR on the tumor cells but do express uPAR on the tumor-associated cells: colon, breast and prostate cancer.
uPAR expression often increases with the grade or stage of tumor and is commonly increased in the secondary (metastatic) malignant tissue.
Research on uPA Targeted Therapy for Cancer
Peptide-based therapies: peptide inhibitors based on the growth factor domain of uPA have shown promising results in both cell culture experiments and in animal models of cancer. Also, peptides that bind to human uPAR, have been shown to hinder tumor growth.
Small-molecule inhibitors: small molecules such as glycinamide inhibitors and oligothiophene derivatives theoretically have potential to target the uPA-uPAR enzyme system for cancer therapy. However, biological data on these compounds has not yet been published and none of these small molecules have undergone preclinical or clinical study.
Monoclonal antibodies: an antibody that targets rat uPAR has been shown to inhibit tumor growth and result in tumor regression in an animal model of breast cancer. Fully human monoclonal antibodies that block uPA binding to uPAR have been shown to inhibit tumor cell invasion and growth. An antibody know as ATN-658, has shown significant inhibition of growth, invasion and metastasis (spread) of a pancreatic cancer cell line and several ovarian cancer cell lines. In animal models of colon cancer and prostate cancer, ATN-658 inhibited tumor growth. ATN-658 is currently in preclinical development for uPA targeted therapy for cancer.
Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy by A.Mazar, in Clinical Cancer Research. 2008, Vol 14, Pages 5649-55.
Evolving role of uPA/uPAR system in human cancers, by K.Dass, A.Ahmad, A.Azmi, S.Sarkar & F.Sarkar, in Cancer Treatment Reviews, 2008, Vol 34, Pages 122-36.