Project Summary/Abstract This project is designed to develop a new approach to monitor and predict treatment response in patients with pancreatic ductal adenocarcinoma (PDA) using hyperpolarized (HP) 13C pyruvate MR molecular imaging. PDA is among the deadliest cancers and is anticipated to become the 2nd leading cause of cancer-related death in the US by 2030. Most PDA patients present with nonresectable disease where systemic therapy is the only life- prolonging treatment. In the minority of patients (~30%) who present with localized, potentially resectable disease, neoadjuvant therapy (NAT) followed by surgery is an emerging approach to improve patient survival but is only beneficial if the selected NAT is effective. For all PDA patients, effective systemic therapy is the single most important factor influencing their survival. However, current response assessment tools, including MRI, CT, and the serum tumor marker CA19-9 provide poor early assessment of response in patients with rapidly lethal advanced PDA, and are suboptimal for selecting patients most likely to benefit from a highly morbid surgery after NAT. Therefore, there is a critical unmet need for more timely and accurate indicators of therapy response in PDA to 1) promptly discontinue ineffective treatments and switch to alternative treatments with potentially better efficacy, and 2) better guide clinical decisions regarding surgery following NAT. Metabolic reprogramming towards increased glycolysis is a hallmark of PDA. In particular, the over-expression of lactate dehydrogenase A and monocarboxylate transporter 1 and 4 results in high levels of pyruvate conversion to lactate, which plays a central role in PDA progression and therapy resistance. Such reprogrammed glycolytic metabolism can be noninvasively interrogated using HP 13C pyruvate MRI, an emerging molecular imaging method that provides dynamic and pathway-specific metabolic information not available with current imaging methods including [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Our preliminary patient studies demonstrate reprogrammed glycolytic metabolism in PDA using HP 13C pyruvate MRI, with increased conversion to lactate and reduced conversion to alanine in tumors compared to normal pancreas. Our preliminary results also suggest that early metabolic changes measured by HP 13C pyruvate MRI can predict tumor response to therapy. Building on these exciting results, we propose to investigate for the first time the value of HP 13C pyruvate MRI for therapy response monitoring in PDA patients. In Aim 1, we will develop and refine HP 13C pyruvate MRI acquisition, post- processing, and analysis strategies optimized for PDA metabolic evaluation. In Aim 2, we will monitor early therapy response using this imaging approach in patients with advanced/nonresectable PDA. In Aim 3, we will determine whether HP 13C pyruvate MRI can predict response to NAT through correlation with pathologic response in patients wi...