THE ROLE AND TARGETING OF INTEGRIN BETA 6 IN PANCREATIC DUCTAL ADENOCARCINOMA

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease characterized by a high mortality rate relative to incidence rate. To date, the therapeutic gold standards for the disease rarely improve median survival, necessitating the exploration of new therapeutic options. One option is to target cancer associated antigens that are specifically upregulated on PDAC cells. In this spirit, we have identified integrin beta 6 (β6) as a potential therapeutic target. We showed that integrin β6 is upregulated in a distinct subset of PDAC tumors and that its expression is linked to cellular proliferative capacity and cell viability. We also explored the mechanism through which these integrin β6 related tumor promoting changes occur. We showed that changes in integrin β6 expression subsequently lead to changes in both phosphorylated extracellular signal-regulated kinases (ERK) and Protein Kinase B (AKT). Furthermore, we showed that a change in the expression of integrin β6 correlates with a change in the in vitro and in vivo tumor initiating capacity and in vitro migratory ability of PDAC cells. Such changes link integrin β6 to the PDAC cancer stem cell (CSC) population and suggest that the targeting of integrin β6 can not only reduce tumor growth, but can also affect the CSC population in the PDAC tumors. In order to target the subset of tumors that express integrin β6, we used a novel inhibition platform known as dual affinity retargeting (DART), which links immune "effector" cells to cancerous "target" cells that express integrin β6. The DART molecule acts by concurrently activating the immune effector cells and facilitating the lysis of the integrin β6 target cells. We showed that this targeting strategy not only reduced cell growth but also reduced the tumor initiating capacity of treated PDAC cells, both in vitro and in vivo. Thus, we investigated the role of a unique PDAC antigen and subsequently targeted it with a novel pharmacologic platform, providing a novel therapeutic strategy for the notoriously deadly PDAC disease