Almost without exception, what kills cancer patients is metastasis, or cancer spread, not the primary tumor. In this context, there is considerable current interest in angiogenesis as a target for development of anti-metastasis therapies. Angiogenesis, the development of new blood vessels, has been shown to be required for tumor growth and metastasis. Extensive laboratory data suggest that angiogenesis plays an essential role in pancreatic cancer development, invasion, and metastasis. Inhibition of angiogenesis could potentially block metastasis formation and the physiological consequences of metastatic growth. Despite advances in cancer therapeutics, it is clear that novel agents with new mechanisms of action are still urgently needed. The goal of this project is to use cutting-edge technologies to develop new therapeutics against pancreatic cancer. While most of the angiogenesis inhibitors under investigation interfere with components of the VEGF pathway, our approach is novel in that it exploits the physical differences between healthy, normal blood vessels and tumor blood vessels, which are weak and poorly formed, enabling the drug to act as a targeted therapy. One of these targets is Vascular Endothelial (VE)-cadherin, a molecule expressed on endothelial cells that line blood vessels. The role of VE-cadherin in the angiogenic process is paramount because it is critical for the proper organization of endothelial cells into vascular tubes, a necessary step for the formation of new blood vessels. Our hypothesis is that despite its ubiquitous distribution throughout both tumor and normal vasculature, VE-cadherin can be selectively targeted during states of pathological angiogenesis because VE-cadherin engagement at junctions, and the type and number of binding domains, might be quantitatively and qualitatively different in tumors. As a result, specific inhibitors of VE-cadherin may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis and tumor damage. Our approach is to use in vitro selection to evolve DNA aptamers (ligands) that bind to VE-cadherin specifically in tumor vasculature, ultimately leading to rupture of tumor vessels. Aptamers have advantages as therapeutics; they distinguish between different functional states of the same protein with high specificity and affinity; they are chemically stable; easily synthesized; and readily modified. If our approach is successful, it will be a powerful addition to our arsenal in the fight against pancreatic cancer. This research employs cutting-edge technologies to develop new anticancer agents that can offer great help to those who suffer from pancreatic cancer. The tumor vasculature specific VE-cadherin aptamers proposed could act as targeted therapeutics that may offer a treatment of the disease, whilst eliminating the unwanted side effects of standard chemotherapy and/or radiotherapy. These novel aptamers also have the potential for a double use, to help monitor the progression or regression of the disease when used as imaging agents. ? ? ?
