Abstract B42: Toward targeting integrin αvβ6 for the therapy of pancreatic cancer.

Abstract

Background: Pancreatic cancer is the fourth leading cause of cancer-related death. Five-year survival rates are less than 3% and haven’t improved over the last 40 years. Thus, novel therapeutic approaches are required urgently. Our clinical and experimental data suggest integrin αvβ6 may be a suitable target. Methods and Results: Bioinformatic studies using the Pancreatic Expression Database revealed that the β6 gene (ITGB6) was highly up regulated in pancreatic ductal carcinoma (PDAC) compared with normal pancreas. Immunohistochemistry analysis showed that normal pancreas lacked αvβ6 expression (n=36) whereas >95% of PDAC tissues (n=192) expressed αvβ6. As these data showed high expression of αvβ6 in PDACs vs. normal pancreas, we investigated its biological role by flow cytometry and western blotting. 8/10 human PDAC cell lines tested expressed αvβ6 and 5/7 αvβ6-positive cell lines exhibited αvβ6-dependent invasion through Matrigel. Antibody-blockade (10μg/ml of rat mAb 53a2) of αvβ6 inhibited cell growth (>65-70%; p=0.0001) in vitro of αvβ6-positive (Panc04.03, CFPac1) but not αvβ6-negative (Panc1, MiaPaca2) PDAC cell lines. Further investigation showed this was due to antibody-induced G2/M cell cycle arrest (IgG - 7.87% vs. 53a2 - 17.5% ) in Panc04.03 and a significant increase in sub-G1 population, indicative of apoptosis (IgG - 9.18% vs. 53a2 - 45.25%) in CFPac1 cell lines after 7day treatment with antibody. These data offer further biological support for recent data (Singh et. al. Cancer Cell, 2009) that reported expression of αvβ6 was required for the growth of PDAC cell lines that are addicted to mutant k-Ras. Conclusion: Thus it appears αvβ6 promotes invasion and growth of PDAC cell lines and represents a promising target for cancer therapy. To this end, we have established novel mouse xenograft models that recapitulate the hypoangiogenic microenvironment of PDAC in humans, in which we are developing preclinical testing of αvβ6-targeted antibody therapy. Citation Format: Sabari Vallath, Emaunela Gadaletta, Claude Chelala, Aldo Scarpa, Ian R. Hart, Hemant M. Kocher, John F. Marshall. Toward targeting integrin αvβ6 for the therapy of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B42.