Pancreatic ductal adenocarcinoma (PDAC) is a rapidly metastasizing cancer of the pancreas. The only treatment options for patients with PDAC are radiation therapy or chemotherapy drugs, both of which can be highly toxic. One hallmark of PDAC is an increase in mitochondrial fission, a process during which mitochondria divide into more numerous, smaller organelles in response to oxidative stress or cell division, both of which are characteristics of KRAS-transformed PDAC. In contrast, healthy cells often have fewer and elongated mitochondria as a result of mitochondrial fusion, a process where mitochondria fuse together in response to damage to facilitate mitochondrial repair or removal. The Taniguchi lab has found by promoting mitochondrial fusion in murine PDAC models, either through genetic manipulation or treatment with leflunomide, an FDA-approved, anti-arthritic drug, oxygen consumption, ATP generation, and tumor growth are reduced, and overall survival increased. Studies are now being expanded to screen a library of FDA-approved drugs for additional activators of mitochondrial fusion that could be rapidly tested in PDAC clinical trials. To inform a future leflunomide PDAC clinical trial, the Taniguchi group will evaluate the therapeutic efficacy of leflunomide as monotherapy as well as in combination with gemcitabine/nab-paclitaxel, which is the current PDAC standard of care chemotherapy. Efficacy studies will be carried out in vitro and in vivo using patient-derived PDAC cell lines and organoids, and correlation of response with KRAS status, as predicted by preliminary data, will be assessed.