Abstract B019: Sensitivity and specificity of detecting premalignant pancreatic lesions by hyperpolarized magnetic resonance
Authors: Enriquez José S , Howell Rian M , Le Roux Olivereen , Pudakalakatti Shivanand , Dutta Prasanta , McAllister Florencia , Bhattacharya Pratip K 
Published: September 2024

Abstract
Introduction: The high mortality rate of pancreatic cancer (PC) results from a lack of methods for early detection. The progression of PC occurs primarily via two precursor pathways, either through microscopic pancreatic intraepithelial neoplasias (PanINs) or macroscopic cystic lesions, of which intraductal papillary mucinous neoplasms (IPMNs) are the most common. The progression from either PanIns or IPMN to PC, provides an opportunity for early detection of this lethal disease. PC cells have extensively reprogrammed metabolism and we have successfully employed hyperpolarized 1-13C pyruvate metabolic imaging (HP MR) to measure non-invasively the metabolic plasticity as the disease initiates and evolves. Concurrently, the specificity of HP MR of detecting premalignant lesions will be determined by imaging pancreatitis induced mice at different timepoints and compare them to the premalignant models. Methods: HP 1-13C Pyruvate MRS was employed to study the metabolic processes in tamoxifen inducible GEM models (P48CreERT2;LSL-KrasG12D (iKC)) with pre-invasive PanIN precursor lesions, invasive PC model (P48CreERT2;LSL-KrasG12D;LSL-p53R172H (iKPC)) and control animals (P48CreERT2 (iC)). These mice were imaged at different time points, before tamoxifen induction, 10-, 20-, and 30-weeks post induction. HP MR was also employed on IPMN mouse model (p48Cre;LSL- KrasG12D;Rosa26R-LSL-rtTA-TetO-GnasR201C) that develop premalignant cystic lesions, that progresses to PC on doxycycline diet (Dox+) for 15 weeks and control mice on normal diet (Dox-). These mice were imaged after 15 weeks of (Dox±) treatment. Simultaneously, wildtype, iC and iKC mice were treated with caerulein for three weeks for the development of pancreatitis and imaged 24 hours after treatment. Results: In the PanIN model, the lactate-to-pyruvate (lac/pyr) ratio increased in the PC models compared to the control model. For the aggressive iKPC mouse model, at the 20-week post induction imaging there was a significant increase of the lac/pyr ratio (0.28±0.04) compared to the 10-week time point (0.22±0.03). At the 20-week time point, the iKPC ratio was higher than the iKC and control ratios, (0.28±0.04 compared to 0.23±0.03 and 0.22±0.02 respectively) indicating the invasive nature of the cancer. Even in the iKC model there is a slight increase of the lac/pyr ratio at 20-weeks (0.23±0.03) compared to control (0.22±0.02). Mice treated with caerulein developed pancreatitis as demonstrated by tissue histology. Surprisingly, the lac/pyr ratio remained constant in both iC and iKC mice that developed pancreatitis, around 0.15±0.03 for both groups. In the IPMN model, IPMN mice feed with doxycycline showed increase pancreatic lesions and an increased lac/pyr ratio (0.43±0.05) compared to mice on normal diet (0.24±0.05). Conclusion: HP MR can detect metabolic shift to lactate in two different models of PC premalignancy representing two different pathways of PC progression. This finding can be potentially translated to the clinic for detection of premalignant pancreatic lesions in high-risk populations.
Citation Format: José S Enriquez, Rian M Howell, Olivereen Le Roux, Shivanand Pudakalakatti, Prasanta Dutta, Florencia McAllister, Pratip K Bhattacharya. Sensitivity and specificity of detecting premalignant pancreatic lesions by hyperpolarized magnetic resonance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B019.