Imaging zinc secretion from the exocrine pancreas for the early diagnosis of pancreatic adenocarcinoma with MRI

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PROJECT SUMMARY/ABSTRACT This proposal aims to use noninvasive molecular magnetic resonance (MR) imaging of pancreatic zinc content and secretion to detect pancreatic intraepithelial neoplasia (PanIN), as early pre-malignant pancreatic ductal adenocarcinoma (PDAC) lesions. It is estimated that 55,440 people in the US will be diagnosed with pancreatic cancer and 45,750 people will succumb to the disease in 2019. Current diagnostic techniques include the use of imaging to localize a lesion and invasive biopsy sampling to stage the cancer and obtain molecular and cellular information from the tumor. Once diagnosed, there are limited treatment options since symptomatic patients will likely already have advanced stage PDAC. Therefore, there is a need to detect PDAC lesions early and in a non-invasive manner. It is known that zinc is stored in zymogen granules in acinar cells at high levels and that zinc homeostasis is uniquely dysregulated in PDAC. We have successfully demonstrated that MR imaging with gadolinium (Gd)-based zinc sensors can report on zinc release from exocrine pancreatic tissue as a response to caerulein stimulation. In this proposal we will evaluate a panel of secretagogues, which are chemical compounds known to stimulate the secretion of zinc from ductal and/or acinar cells in the exocrine pancreas, to optimize their ability to generate zinc flux detectable with our molecular MR probe. I will then use this cell-specific metabolic zinc imaging technique to noninvasively quantify the zinc homeostatic dysregulation in pancreatic cancer mouse models by MRI. Elucidating the role of zinc homeostasis in the development of pancreatic adenocarcinoma by non-invasively measuring zinc release from acinar and ductal cells as a response to their natural secretagogues will allow us to identify biomarkers that report on molecular transformations early in the disease. This in turn could then enable patients to obtain a diagnosis at an early stage and thus have access to more effective therapies and curative surgical options. The short-term goal of this project is to optimize and characterize the stimulated zinc secretion in the exocrine pancreas and its detection in vivo with molecular MRI to identify early malignant transformations in PDAC, in doing so I will obtain the training from my advisory committee, who are experts in the field of pancreatic cancer molecular pathogenesis, histopathology, surgery, and radiology. Attaining my short-term goal will enable me to obtain expertise in the following areas: 1) Clinical pathology techniques for diagnosis of pancreatic adenocarcinoma. 2) Biomarker identification and validation. 3) Metabolic implications of zinc homeostasis in PDAC pathogenesis. This project will also allow me to generate data that will enhance my probability of success in obtaining independent NIH grant support. With the skills and knowledge obtained as a result of the research and training activities from this proposal, I will be able to reach my long-term goal of becoming an independent translational investigator using MRI to infer key metabolic, biological, and physiological characteristics of cancer pathogenesis based on metal homeostasis.