While
pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of
pancreatic cancer may result in improved outcomes and therefore, methods for early detection of
cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial
neoplasias (PanINs) have been identified as premalignant precursor lesions to
pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede
pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing
alanine/
lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of
alanine and
lactate metabolites with
disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C]
pyruvate. The
alanine-to-
lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of
alanine transaminase (ALT) and
lactate dehydrogenase (LDH)
enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging
biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.