Abstract 4215: Hyperpolarized magnetic resonance metabolic imaging and NMR metabolomics to assess the progression and aggressiveness of patient-derived pancreatic cancer xenografts

Abstract

Abstract Pancreatic cancer, the most lethal of solid tumors is an aggressive disease that develops relatively symptom-free. The absence of early symptoms has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic intervention to improve the survival rate of pancreatic cancer patients. Our goal is to identify metabolic biomarkers for early detection with an understanding of pancreatic cancer progression from benign lesions to a malignant state. Hyperpolarized magnetic resonance imaging (HP-MRI) provides a >10,000-fold signal enhancement for detecting of endogenous metabolic substrates to monitor metabolic fluxes through the multiple key biochemical pathways including glycolysis and citric acid cycle. In particular, conversion between hyperpolarized 13C-labeled pyruvate and lactate, catalyzed by lactate dehydrogenase (LDH), has been shown to have a number of potential applications such as diagnosis, staging tumor grade and monitoring therapy response. Genetic mutation is evident in causing tumorigenesis and often time these mutations trigger the signaling pathways that are associated with “metabolic transformations. There is currently tremendous research interest in dissecting the mechanisms of metabolic transformation as the cancers progress. In this effort, we are applying high-resolution NMR (nuclear magnetic resonance) metabolomics and the real-time hyperpolarized metabolic imaging of patient-derived xenograft tumors for probing the underlying mechanism of altered-metabolism and correlate with pancreatic cancer progression and its aggressiveness. The protocol detailing heterotopic engraftment of pancreatic cancer patient tumors into immunodeficient mice and expansion of direct xenograft tumors was recently reported elsewhere. These patient-derived xenografts (PDX) were well annotated with original patient tumors. For the NMR metabolomics study, the fresh-frozen tumor samples were homogenized, lyophilized, and resuspended in D2O and 1-D proton NMR spectroscopy was employed to characterize the water-soluble portion of the metabolome. These data suggest that elevated glycolysis (production of high lactate) and alterations in choline metabolism may arise in pancreatic cancer development. Also, the metabolite concentrations were significantly higher in aggressive tumors compare to non-aggressive one. The real-time metabolic imaging shows the immediate conversion of lactate after injection (i.v.) of hyperpolarized 13C pyruvate and probe the upregulated LDH activity as the cancer progress. The basic genomic profiling of these tumors is in progress. This model may provide an excellent platform where mutational status of these patient tumors can be correlated with both high resolution and hyperpolarized dynamical metabolomics data for characterizing individual tumor phenotypes. Citation Format: Prasanta Dutta, Mayrim Rios Perez, Travis Cole Salzillo, Michael Pratt, Yaan Kang, Niki Zacharias, Anirban Maitra, Jason B. Fleming, Pratip Bhattacharya. Hyperpolarized magnetic resonance metabolic imaging and NMR metabolomics to assess the progression and aggressiveness of patient-derived pancreatic cancer xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4215.