Unlocking early pancreatic cancer detection through zinc sensitive metabolic MRI

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT This proposal will develop a non-invasive molecular magnetic resonance imaging (MRI) biomarker to detect pancreatic ductal adenocarcinoma (PDAC) by imaging dysregulated pancreatic zinc secretion. PDAC is the most common pancreatic malignancy and remains highly lethal because most patients are diagnosed at advanced stages, when curative resection is no longer possible. Current imaging and surveillance strategies rely on CT, magnetic resonance cholangiopancreatography (MRCP), and serum Ca19-9, which have limited sensitivity for small lesions and substantial false positivity. There is therefore a critical need for a sensitive, non-invasive method to detect PDAC earlier and to better assess treatment response. Zinc is stored at high levels in zymogen granules of pancreatic acinar cells, and zinc homeostasis is uniquely altered in PDAC. We developed secretagogue-stimulated zinc-secretion MRI (SSZS-MRI), which measures transient hormone-evoked extracellular Zn release from the exocrine pancreas. Importantly, this hypersecretory phenotype is confined to the tumor-bearing pancreas: tumor-adjacent parenchyma shows a robust MRI response, whereas healthy pancreas and pancreatitis controls show minimal or no signal change under the same stimulus. Because the readout arises from pancreatic parenchyma rather than the tumor itself, SSZS-MRI can identify abnormal exocrine physiology without requiring direct visualization of small or elusive lesions. T1 mapping of the tumorbearing pancreas will serve as the primary endpoint. We will: 1) define robustness across sex, age, diet, and PDAC models; 2) establish decision thresholds for treatment response and early recurrence across chemotherapy, radiation, and KRASG12D inhibition/withdrawal, benchmarked against multiparametric MRI and RECIST readouts; and 3) perform human feasibility studies using precision-cut pancreatic tissue slices with LA-ICP-MS zinc mapping and acinar viability/function assays. Vertebrate animal models are essential because only intact in vivo PDAC models can capture pancreas-wide secretagogue-evoked zinc secretion, probe delivery, tumor-host interactions, and longitudinal treatment response and recurrence in a physiological setting. Orthotopic and transgenic mouse models complement human tissue studies by enabling controlled testing of biological and therapeutic variables that cannot be reproduced in resected human tissue slices alone. Successful completion will establish SSZS-MRI as a quantitatively validated, biology-anchored functional biomarker that complements current imaging and could enable earlier, more informed clinical decisions in PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is ranked as the fourth leading cause of cancer-related death in the United States with 1 - and 5-year survival rates of 25% and 5%, respectively. We found that zinc content and secretion is dysregulated in pancreatic cancer, and that the degree of dysregulation follows malignant progression. This work proposes a non-invasive technique to detect early malignant transformations in pancreatic cancer using exogenous secretagogues and an MRI zinc probe to image zinc dysregulation in vivo.