Abstract
Hyaluronan (HA) is a non-sulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and ligands, and to mediate a number of cellular functions as well as disease progression. Studies have shown that binding of HA to CD44 in cancer cells activates survival pathways resulting in cancer cell survival. This effect can be blocked by anti-CD44 monoclonal antibodies. A6 is a capped, eight l-amino acid peptide (Ac-KPSSPPEE-NH2) derived from the biologically active connecting peptide domain of the serine protease, human urokinase plasminogen activator (uPA). A6 neither binds to the uPA receptor (uPAR) nor interferes with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and metastasis of tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of diabetic retinopathy and wet age-related macular degeneration through the reduction of retinal vascular permeability and inhibition of choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with chronic lymphocytic leukemia expressing the kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease.
Highlights
Mortality due to cancer is generally the result of metastasis of the primary tumor
Metastasis and recurrence have been linked to a subpopulation of highly invasive tumorigenic cells that are characterized by the expression of CD44
Metastasis and recurrence have been linked to a subpopulation of highly invasive tumorigenic cells, which have been shown to be resistant to chemotherapeutics
Summary
Mortality due to cancer is generally the result of metastasis of the primary tumor. Recurrence at distant sites following first-line therapy continues to be a major challenge. The biological importance of the connecting peptide domain (amino acid residues 132–158) has been further demonstrated by the phosphorylation or substitution of serine 138, which results in the inhibition of uPA-induced cell migration without changing uPA binding to uPAR [12, 13]. Phosphorylation or substitution of uPA serine 138 does not change the growth factor domain-mediated binding of uPA to uPAR, yet inhibits migration, which suggests that the connecting peptide domain region is important for regulatory function. This indicates that simultaneous concurrent interaction of uPA domains, with distinct surface receptors, is required for uPARdependent cell migration. The evaluation of A6 activity using alanine scanning mutagenesis demonstrated that there is a degree of substitution that can be accommodated without a substantial loss of A6 activity, and analysis of the CD44 homologous peptide sequence revealed activity similar to that of A6 [22]
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