PR000680 (Project)

Description:Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately one third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder, and disappointing results from recent Phase III clinical trials indicate that a cachexia treatment is not likely to appear soon. Thus, it is clear that greater knowledge of the mechanisms driving muscle wasting in cachexia is needed in order to identify new therapeutic targets and stimulate new clinical trials. Our approach to gaining this knowledge has been to work with muscle biopsies from pancreatic cancer patients, since this population is highly prone to cachexia. We have also been expanding our studies beyond the classical mouse models of cancer cachexia in hopes of finding a new model that better recapitulates the human disease. We recently undertook RNA-Seq analysis comparing muscle biopsies from pancreatic cancer patients with and without cachexia, which has been exciting since this type of analysis has not yet been performed in patient samples. Preliminary results revealed that cachectic muscle was associated with alterations in metabolism. These data provide the rationale for performing metabolomics to ascertain whether specific metabolic pathways or metabolites can be identified as potential drivers of muscle wasting in cachexia or be used as biomarker of cachexia, which the field desperately needs. An additional need is a well-validated animal model of cancer cachexia that accurately reflects the human condition, which can be used to test mechanisms and pre-clinical compounds. We propose to perform these studies under the Mayo Clinic Metabolomics Resource Core Pilot and Feasibility Grant program to: 1) Identify metabolic alterations and biomarkers of pancreatic cancer-induced muscle wasting; and 2) Identify a suitable mouse model that recapitulates the metabolic imbalance of muscles from pancreatic cancer cachexia patients. By performing these studies, we will accelerate our understanding of the underlying causes of muscle wasting, which should translate to improving the current pipeline of anticachexia therapies.