Abstract #713: Characterization of a new candidate target for pancreatic cancer immunotherapy: Tyrosine phosphorylation regulates cell surface translocation of Annexin A2 and contributes to pancreatic cancer invasion
Authors: Lei Zheng, Lanqing Huang, Guanglan Mo, Theodore Kouo, Rajni Sharma, Peter Illei, Daniel Laheru, Elizabeth Jaffee
Journal: Cancer Research (2009)

Pancreatic adenocarcinoma (PDA) is a devastating cancer with a high mortality rate and few treatment options. Novel biomarkers and therapeutic targets are desperately needed to facilitate the early diagnosis and improve the treatment options for this disease. Cancer immunotherapy is an emerging approach for the treatment of PDA. Additionally, it provides critical human reagents for developing methods to identify new candidate proteins and biologic pathways. We previously developed an allogeneic GM-CSF secreting vaccine approach for the treatment of patients with resected PDA to prevent early recurrence. Phase I and II trials evaluating this vaccine in patients with resected PDA demonstrated both clinical and immunologic responses. We used immunized sera from these patients to develop a functional proteomic approach to identify pancreatic tumor proteins that are the targets of vaccine induced humoral responses. Annexin A2 (ANXA2), a member of the Annexin family of calcium-dependent, phospholipid binding proteins, is the first of a panel of identified antigens recognized by the post-vaccination sera of patients who demonstrated prolong disease-free survival following multiple vaccinations. An analysis of 16 patients in the phase II PDA vaccine study showed that vaccine induced anti-Annexin A2 antibody was detected in 6 of 8 patients who demonstrated an overall survival longer than 36 months, and only in 1 of 8 patients who did not demonstrate long-term survival. This result provides the first evidence that Annexin A2 is a potential pancreatic cancer tumor associated antigen. Consistent with previous reports, this study found that Annexin A2 is abundantly expressed in PDA and that Annexin A2 expression on the cell surface increases with the progression from premalignant lesions to invasive PDA. Immunohistochemistry analysis showed that 29 (72.5%) out of 40 pancreatic tumor tissue samples tested have a significantly increased cell surface expression of Annexin A2. We further demonstrated that knock-down of Annexin A2 by siRNA suppressed the in vitro invasion of PDA cells and suggested that the cell surface localization of Annexin A2 is critical for PDA cell invasion. Moreover, phosphorylation of Annexin A2 at Tyrosine 23 is indispensible for its localization to the cell surface and for the invasion of PDA cells. Finally, this study demonstrated that loss of Annexin A2 leads to the loss of the TGF\#946;-induced epithelial to mesenchymal transition in PDA cells, providing a mechanism to explain why loss of Annexin A2 inhibits the invasion capacity of PDA cells. Taken together, Annexin A2 plays an important role in PDA cell invasion; and Annexin A2 is a new candidate pancreatic cancer therapeutic target for the future development of monoclonal antibody, small molecule, and vaccine therapies.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 713.