BMC Cancer Research article The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer Sean P Dineen1,2, Laura A Sullivan1,2, Adam W Beck1,2, Andrew F Miller1,2, Juliet G Carbon1,2, Roni Mamluk3, Henry Wong3 and Rolf A Brekken*1,3,4 BioMed Central Open Access Address: 1Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical School, Dallas, TX 75390-8593, USA, 2Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical School, Dallas, TX 75390-8593, USA, 3Adnexus, a Bristol-Myers Squibb Company, Waltham, MA 02453, USA and 4Department of Pharmacology, University of Texas Southwestern Medical School, Dallas, TX 75390-8593, USA Email: Sean P Dineen - SDINEE@parknet.pmh.org; Laura A Sullivan - laura.payton@utsouthwestern.edu; Adam W Beck - awbeck01@yahoo.com; Andrew F Miller - andyfmiller@gmail.com; Juliet G Carbon - juliet.carbon@utsouthwestern.edu; Roni Mamluk - roni@chiasmacorp.com; Henry Wong - hwong@adnexustx.com; Rolf A Brekken* - rolf.brekken@utsouthwestern.edu * Corresponding author Published: 27 November 2008 BMC Cancer 2008, 8:352 doi:10.1186/1471-2407-8-352 This article is available from: http://www.biomedcentral.com/1471-2407/8/352 Received: 26 August 2008 Accepted: 27 November 2008 © 2008 Dineen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2. Methods: The efficacy of CT-322 was evaluated in vivo using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M). Results: Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice. Conclusion: We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted. Page 1 of 10 (page number not for citation purposes)