Abstract 5258: 1 H MRS analysis of pancreas metabolites altered by cachexia

Abstract

Abstract Cachexia is a multifactorial syndrome characterized by skeletal muscle weight loss and reduced physical activity. The extreme weight loss due to cachexia results in a particularly poor quality of life causing profound weakness, listlessness, and inability to function [1, 2]. Severe weight loss decreases the tolerance to treatments and anticancer therapies, and leads to the reduced survival of patients. In pancreatic cancer, the syndrome affects nearly 80% of patients [3]. Cancers can stimulate cachexia through the dysfunction of multiple organs [4]. Metabolic abnormalities may interfere with the regular functioning of these organs to increase the severity of the disease. Here we determined metabolic changes in the pancreas with cachexia-inducing and non-cachexia inducing tumor growth using high-resolution quantitative 1H magnetic resonance spectroscopy (MRS) of pancreas tissue obtained from normal, non-cachectic (Panc1) and cachectic (Pa04C) mice bearing pancreatic ductal adenocarcinoma (PDAC) xenografts. Cancer cells were inoculated in the right flank of six to eight week old male severe combined immunodeficient mice. The pancreas was removed from mice following euthanization once tumors were ~300 mm3, snap frozen and stored at -80°C prior to dual phase extraction. 1H MRS was performed on the water phase. All 1H MR spectra with water suppression were acquired on a 750 MHz MR spectrometer using a single pulse sequence. All data processing analyses and quantification were performed with TOPSPIN 3.5 software. All statistical analysis were performed with MetaboAnalyst software [5]. Multivariate analyses performed to analyze the differences in the metabolic profiles among the groups (Control n = 9, Pa04C = 10 and Panc1 = 8) revealed differences in the overall metabolic pattern in the pancreas from normal, cachectic and non-cachectic groups. A significant decrease of leucine, isoleucine, valine, BCAA, glutamate, choline, pyruvate, glycine, niacinamide, fumarate and increase of alanine, pyruvate, and NAD was detected in cachectic mouse pancreas compared to control pancreas. A significant increase in alanine, phenylalanine, pyruvate, phosphocholine and decrease in glycine, NAD, niacinamide was observed in cachectic mouse pancreas compared to non-cachectic mouse pancreas. Pathway impact analysis using MetaboAnalyst web software indicated alterations in branch chain amino acid pathways and glutamate, glutamine metabolism. These results provide new insights into changes in pancreas metabolism with cachexia, and support investigating metabolic targets and biomarkers to reduce cachexia-associated morbidity. Supported by NIH R01CA193365 and R35CA209960. Ref: 1. Fearon K et al, The Lancet Oncology. 2011; 2. Penet MF, Bhujwalla ZM. Cancer journal. 2015; 3. Winnard PT, Jr. et al, Cancer research. 2016; 4. Argiles JM et al, Nature reviews Cancer. 2014; 5. Xia J, Wishart DS. Nature protocols. 2011. Citation Format: Raj Kumar Sharma, Santosh K. Bharti, Paul T. Winnard Jr, Yelena Mironchik, Marie-France Penet, Zaver M. Bhujwalla. 1 H MRS analysis of pancreas metabolites altered by cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5258.