Abstract 370: Hyperpolarized magnetic resonance metabolic imaging in pancreatic cancer research: Early detection, assessing aggressiveness and real-time monitoring treatment response

Abstract

Abstract Pancreatic cancer is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated pathways and the unique physiology of the tumor microenvironment. In our research, we are interrogating reprogrammed metabolism in pancreatic cancer. We have employed hyperpolarized metabolic imaging to measure noninvasively the metabolic plasticity as the diseases initiate, evolve and respond to the drugs. Genetically engineered mouse (GEM) model with progression of pancreatic intraepithelial neoplasm (PanIN) lesions has been used for early detection, patient-derived xenografts (PDX) model to assess aggressiveness, and orthotopic pancreatic cancer model for monitoring metabolically targeted therapeutic response. Hyperpolarization of pyruvate and in-vivo 13C MRS were performed using Hypersense (Oxford Instruments) and 7T MRI scanner with a dual tuned 1H/13C volume coil (Bruker), respectively. Tissue alanine and lactate concentrations were determined using a Bruker 500 MHz NMR spectrometer coupled with cryoprobe. Histology and immunohistochemistry were performed on excised tissue samples. Hyperpolarized pyruvate metabolism in PDX tumor was well captured in real time. Pyruvate was readily metabolized to lactate and alanine in vivo. The quantitative flux ratios lactate-to-pyruvate (Lac/Pyr) and alanine-to-lactate were determined. The most aggressive tumors showed the highest value of Lac/Pyr ratio. GEM model such as P48Cre;LSLKrasG12D mice were used for detection of early and advanced PanIN, which usually develop in these mice between 20 and 25 weeks. The imaging experiments were performed at the different stages of the disease. Progression of disease from tissue containing predominantly low-grade PanIN to tissue with high-grade PanIN showed a decreasing alanine/lactate concentration ratio as measured by 1H-NMR metabolomics. These results demonstrate that there are significant alterations of alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities that favor the transformation of aggressive pancreatic cancer from PanIN lesion. The efficacy of a metabolically targeted drug was monitored in orthotopic pancreatic cancer mice by measuring flux ratio of Lac/Pyr after injecting hyperpolarized pyruvate before the tumor shrinkage. Metabolic imaging with hyperpolarized pyruvate and NMR metabolomics enabled detection and monitoring of the progression of pancreatic cancer lesions. Translation of this HP-MRI technique to the clinic has the potential to improve early detection and the management of patients' care. Citation Format: Prasanta Dutta, Erick Riquelme Sanchez, Yu Zhang, Travis Salzillo,, Priyank Raj, Jaehyuk Lee, Niki Millward, Anirban Maitra, Florencia McAllister, Pratip Bhattacharya. Hyperpolarized magnetic resonance metabolic imaging in pancreatic cancer research: Early detection, assessing aggressiveness and real-time monitoring treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 370.