Pancreatic cancer continues to carry a poor prognosis, with a 5-year survival rate of approximately five percent . As patients typically present at an advanced stage, new chemotherapeutic strategies are necessary to improve the dismal prognosis associated with this disease. Angiogenesis is a hallmark of cancer  and is required for cancer growth beyond 1–2 mm3 [2, 3]. Vascular endothelial growth factor A (VEGF) is the best characterized member of the VEGF family of growth factors. VEGF is a potent angiogenic factor expressed during development and in tumors [4, 5]. The effects of VEGF are mediated by binding to one of its two receptors VEGF receptor 1 or 2 (VEGFR1, VEGFR2) [4, 6]. Tumor angiogenesis is driven primarily by VEGF:VEGFR2 interaction [5, 6]. The effect of VEGFR1 activation is less understood, but is thought to be involved in macrophage chemotaxis [5–7].
The complexity of the VEGF pathway allows for multiple targets for inhibiting tumor angiogenesis [5, 8]. For example, bevacizumab (Avastin®, Genentech, Inc., South San Francisco, CA) is a monoclonal antibody to human VEGF which binds VEGF and blocks its interaction with both VEGFR1 and VEGFR2 . Bevacizumab has been shown to be effective in combination with chemotherapy for the treatment of metastatic colorectal cancer and non-small cell lung cancer [10, 11]. Receptor tyrosine kinase inhibitors have also been developed which inhibit the VEGF receptors [5, 8]. These small molecules penetrate into cells and, unlike antibodies, inhibit multiple members of the VEGF receptor family. This broad spectrum of inhibition may lead to different side effect profiles from monoclonal antibodies .
There are a variety of proteins being developed as new biologic drugs beyond the traditional biologic class of monoclonal antibodies . Adnectins are a new class of targeted biologics among the most advanced of such proteins. Adnectins are well-suited to pharmaceutical discovery and development, based on preclinical data [13, 14]. These small proteins are derived from the 10th type III domain of human fibronectin, an extracellular protein that is abundant in human serum and the extracellular matrix, and naturally binds to other proteins [13, 14]. By changing the amino acid sequence of three targeting loops clustered at one end of the protein, an Adnectin can be designed to bind to a specific disease target, such as a receptor, ligand or protein with nanomolar or picomolar affinity, and potency and specificity comparable to or better than antibodies. One such Adnectin has been developed that binds to VEGFR2. This construct, CT-322, has been shown previously to block the activity of murine and human VEGFR2 in vitro .
In the present study, we were interested in whether this novel compound would block tumor angiogenesis and subsequent growth in an orthotopic model of pancreatic cancer. In the following experiments, we demonstrate that CT-322 is effective at treating pancreatic tumors in two animal models, that CT-322 blocks tumor angiogenesis and that treatment with CT-322 induces tumor destruction.