Pancreatic cancer is the 4th leading cause of cancer-related death in Canada, and has the highest mortality rate of all major cancers. Pancreatic cancers are characterized by a unique microenvironment, deficient in blood vessels and oxygenation (hypoxia). These features contribute to the aggressive nature of pancreatic cancer and its resistance to treatment. Our group has identified important new signalling pathways essential for hypoxic cell survival and treatment response. In this proposal, we hypothesize that these pathways can be targeted with new therapies and have set out 3 aims to translate these findings. In Aim 1 we will explore the biological mechanisms that underlie the importance and synergies of two novel signalling pathways that protect hypoxic pancreatic cells against cell death. In Aim 2, we will test the potential of targeting different components of the pathways in combination using new pancreatic models derived directly from patients. In aim 3, we will conduct pre-clinical studies to test currently available drugs that target these novel pathways in combination with current standard of care. The studies are designed to prepare for the launch of personalized medicine trials targeting hypoxia in pancreatic cancer.