Molecular MRI of Dysregulated Zinc Secretion Detects Pancreatic Ductal Adenocarcinoma and Response to KRAS G12D Inhibitor Treatment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, primarily because of late-stage diagnosis and limited treatment options. Zinc homeostasis is markedly dysregulated in PDAC, and this dysregulation can be probed by administering a secretagogue to stimulate zinc secretion (SSZS) in the exocrine pancreas and imaging with a zinc-sensitive MRI probe. This study demonstrated the potential of SSZS-MRI for sensitive detection, monitoring treatment response, and assessing recurrence after treatment withdrawal in PDAC. The approach relied on interrogating the pancreas, circumventing the challenge of locating small, elusive tumors. SSZS-MRI enabled PDAC detection by observing the unique zinc hypersecretory activity of the pancreas when malignancy was present. PDAC led to dysregulation of zinc transporters in both human and mouse pancreas. Combining secretagogues such as secretin and caerulein maximized zinc secretion and MRI signal in the pancreas. Notably, SSZS-MRI detected treatment responses to KRASG12D inhibition within 3 to 5 days and identified cancer recurrence as early as 1 day after treatment withdrawal. Additionally, secretagogue stimulation improved treatment responses and delayed recurrence in both treatment models. These findings suggest that SSZS-MRI could significantly enhance PDAC diagnosis and management, providing an imaging modality that can help optimize patient outcomes. Significance: Secretagogue-stimulated zinc secretion MRI is effective at detecting pancreatic cancer, monitoring treatment response, and determining cancer recurrence, offering a promising noninvasive imaging tool to improve patient management and outcomes.