Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States, largely because most patients are diagnosed only after the disease has reached an advanced stage at which it is extremely difficult to treat. harbor activating KRAS mutations, and genetically engineered mouse models have shown that oncogenic Kras signaling is essential for PanIN initiation, maintenance, and progression to invasive cancer. These discoveries, coupled with the recent clinical success of RAS(ON) inhibitors that directly target mutant KRAS, create a compelling opportunity to intervene before malignant transformation occurs. However, PanIN lesions are not visible with conventional imaging, leaving a major unmet need for tools that can detect and eliminate early disease in the native pancreas.
This project will build a new platform for pancreatic cancer interception by combining mutant KRAS inhibition with next-generation molecular imaging. The investigators will determine how small-molecule RAS(ON) inhibitors can eliminate PanINs and prevent tumor development in genetically engineered mouse models, laying the groundwork for therapeutically ablating precancerous lesions in vivo. They will also synthesize radiolabeled RAS(ON) inhibitors to enable positron emission tomography-based detection of mutant KRAS activity, with the goal of developing a sensitive, noninvasive method to quantify PanIN burden over time. Finally, the team will evaluate PanIN biology in patients with resectable pancreatic cancer who receive neoadjuvant RAS(ON) inhibitor therapy, providing the first direct assessment of how these agents affect precursor lesions in human tissue. Ultimately, this work aims to transform the clinical landscape for PDAC by introducing new molecular strategies to both visualize and eradicate preneoplastic disease before it progresses to a lethal malignancy.