Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat. Mutations in the KRAS gene that are found in almost all PDAC tumors are widely considered to be undruggable, and there are currently no effective immunotherapies for PDAC. Researchers in the Cantley and Lyssiotis labs are investigating a new drug target in PDAC by exploiting the fact that PDAC cells produce elevated levels of cell-damaging reactive oxygen species (ROS). PDAC tumors have evolved an altered metabolism to compensate for this increase in ROS levels. The researchers have generated evidence suggesting that targeting a specific metabolic pathway may disrupt this compensatory process and suppress tumor growth without harming healthy tissue. In preliminary studies, they identified a genetic signature that identifies tumors likely to be especially sensitive to this type of inhibition. In this project, the researchers will take the first steps toward developing small molecules that target this pathway to evaluate the safety and efficacy of this approach. The researchers will genetically engineer PDAC cells derived from patients to either suppress or hyper-stimulate this metabolic pathway and then test tumors grown from these cell lines for their sensitivity to the small molecule inhibitors. They will also assess the behavior, physical condition, and immune function of adult mice in which this metabolic pathway has been genetically ablated to identify potential safety concerns. This research could lead to new anti-cancer drugs that can be used alone or in combination with immunotherapy to treat a subset of PDAC patients with sensitive tumors.