#METABOLOMICS WORKBENCH hormel101_20180715_120404_mwtab.txt DATATRACK_ID:1450 STUDY_ID:ST001013 ANALYSIS_ID:AN001655 PROJECT_ID:PR000680 VERSION 1 CREATED_ON July 17, 2018, 12:49 pm #PROJECT PR:PROJECT_TITLE Mayo Pilot and Feasibility: Metabolomics of Muscle Wasting in Cancer Cachexia PR:PROJECT_SUMMARY Cachexia is a debilitating syndrome that results in severe, involuntary weight PR:PROJECT_SUMMARY loss due to the depletion of skeletal muscle mass. This syndrome occurs in a PR:PROJECT_SUMMARY majority of cancers and contributes to approximately one third of all cancer PR:PROJECT_SUMMARY deaths. Currently, no effective therapy exists to combat this malignant PR:PROJECT_SUMMARY disorder, and disappointing results from recent Phase III clinical trials PR:PROJECT_SUMMARY indicate that a cachexia treatment is not likely to appear soon. Thus, it is PR:PROJECT_SUMMARY clear that greater knowledge of the mechanisms driving muscle wasting in PR:PROJECT_SUMMARY cachexia is needed in order to identify new therapeutic targets and stimulate PR:PROJECT_SUMMARY new clinical trials. Our approach to gaining this knowledge has been to work PR:PROJECT_SUMMARY with muscle biopsies from pancreatic cancer patients, since this population is PR:PROJECT_SUMMARY highly prone to cachexia. We have also been expanding our studies beyond the PR:PROJECT_SUMMARY classical mouse models of cancer cachexia in hopes of finding a new model that PR:PROJECT_SUMMARY better recapitulates the human disease. We recently undertook RNA-Seq analysis PR:PROJECT_SUMMARY comparing muscle biopsies from pancreatic cancer patients with and without PR:PROJECT_SUMMARY cachexia, which has been exciting since this type of analysis has not yet been PR:PROJECT_SUMMARY performed in patient samples. Preliminary results revealed that cachectic muscle PR:PROJECT_SUMMARY was associated with alterations in metabolism. These data provide the rationale PR:PROJECT_SUMMARY for performing metabolomics to ascertain whether specific metabolic pathways or PR:PROJECT_SUMMARY metabolites can be identified as potential drivers of muscle wasting in cachexia PR:PROJECT_SUMMARY or be used as biomarker of cachexia, which the field desperately needs. An PR:PROJECT_SUMMARY additional need is a well-validated animal model of cancer cachexia that PR:PROJECT_SUMMARY accurately reflects the human condition, which can be used to test mechanisms PR:PROJECT_SUMMARY and pre-clinical compounds. We propose to perform these studies under the Mayo PR:PROJECT_SUMMARY Clinic Metabolomics Resource Core Pilot and Feasibility Grant program to: 1) PR:PROJECT_SUMMARY Identify metabolic alterations and biomarkers of pancreatic cancer-induced PR:PROJECT_SUMMARY muscle wasting; and 2) Identify a suitable mouse model that recapitulates the PR:PROJECT_SUMMARY metabolic imbalance of muscles from pancreatic cancer cachexia patients. By PR:PROJECT_SUMMARY performing these studies, we will accelerate our understanding of the underlying PR:PROJECT_SUMMARY causes of muscle wasting, which should translate to improving the current PR:PROJECT_SUMMARY pipeline of anticachexia therapies. PR:INSTITUTE Mayo Clinic PR:LAST_NAME Guttridge PR:FIRST_NAME Denis PR:ADDRESS 520 Biomedical Research Tower 460 W. 12th Avenue Columbus, OH 43210 PR:EMAIL denis.guttridge@osumc.edu PR:PHONE 614-688-3137 #STUDY ST:STUDY_TITLE TCA Concentrations in Serum for Muscle Wasting in Cancer Cachexia (part-VIII) ST:STUDY_SUMMARY TCA Concentrations of Muscle Wasting in Cancer Cachexia. Serum samples from 10 ST:STUDY_SUMMARY control patients, 10 weight stable pancreatic cancer patients, and 10 pancreatic ST:STUDY_SUMMARY cancer patients with significant weight loss. Samples are divided evenly between ST:STUDY_SUMMARY males and females. ST:INSTITUTE Mayo Clinic ST:LAST_NAME Guttridge ST:FIRST_NAME Denis ST:ADDRESS 520 Biomedical Research Tower 460 W. 12th Avenue Columbus, OH 43210 ST:EMAIL denis.guttridge@osumc.edu ST:PHONE 614-688-3137 #SUBJECT SU:SUBJECT_TYPE Human SU:SUBJECT_SPECIES Homo sapiens SU:TAXONOMY_ID 9606 #SUBJECT_SAMPLE_FACTORS: SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Additional sample data SUBJECT_SAMPLE_FACTORS - Sample # 1 Grouping:Weight Losing | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 2 Grouping:Control | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 3 Grouping:Control | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 4 Grouping:Control | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 5 Grouping:Weight Losing | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 6 Grouping:Weight Losing | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 7 Grouping:Control | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 8 Grouping:Weight Stable | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 9 Grouping:Control | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 10 Grouping:Control | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 11 Grouping:Weight Stable | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 12 Grouping:Weight Stable | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 13 Grouping:Weight Losing | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 14 Grouping:Weight Losing | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 15 Grouping:Control | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 16 Grouping:Weight Stable | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 17 Grouping:Weight Stable | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 18 Grouping:Control | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 19 Grouping:Weight Stable | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 20 Grouping:Control | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 21 Grouping:Weight Losing | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 22 Grouping:Weight Losing | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 23 Grouping:Weight Stable | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 24 Grouping:Weight Stable | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 25 Grouping:Weight Stable | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 26 Grouping:Weight Losing | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 27 Grouping:Control | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 28 Grouping:Weight Stable | Gender:Male Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 29 Grouping:Weight Losing | Gender:Female Sample type=Serum; Species=Human SUBJECT_SAMPLE_FACTORS - Sample # 30 Grouping:Weight Losing | Gender:Male Sample type=Serum; Species=Human #COLLECTION CO:COLLECTION_SUMMARY Tissue and blood donated from Cancer Cachexia Program at Ohio State University CO:SAMPLE_TYPE Blood (serum) #TREATMENT TR:TREATMENT_SUMMARY "Cancer cachexia is a multi-factorial syndrome accompanying advanced cancer, TR:TREATMENT_SUMMARY with the most notable symptom being unintentional weight loss. Cachectic TR:TREATMENT_SUMMARY patients lose both adipose tissue and skeletal muscle, with skeletal muscle loss TR:TREATMENT_SUMMARY and its associated weakness contributing to the morbidity and mortality of these TR:TREATMENT_SUMMARY patients. Despite three decades of research into mechanisms driving muscle TR:TREATMENT_SUMMARY wasting due to cancer, to date, an approved pharmacological therapy to prevent TR:TREATMENT_SUMMARY or treat cancer cachexia is still lacking. Our laboratory focuses on cancer TR:TREATMENT_SUMMARY cachexia in patients with pancreatic cancer, as up to 85% of these patients TR:TREATMENT_SUMMARY experience weight loss. Cachexia often occurs early in the progression of TR:TREATMENT_SUMMARY pancreatic cancer, making clear that cachexia in these patients is not simply a TR:TREATMENT_SUMMARY result of end-stage disease. Further, with perhaps more than ¼ of all TR:TREATMENT_SUMMARY pancreatic cancer deaths resulting from muscle weakness as opposed to tumor TR:TREATMENT_SUMMARY burden, cachexia also significantly contributes to mortality due to pancreatic TR:TREATMENT_SUMMARY cancer. Because little progress has been made in improving treatment outcomes, TR:TREATMENT_SUMMARY addressing cancer-induced muscle wasting is perhaps the best strategy to prolong TR:TREATMENT_SUMMARY pancreatic cancer patient survival and increase patient quality of life. In an TR:TREATMENT_SUMMARY effort to better understand the mechanisms driving pancreatic cancer-induced TR:TREATMENT_SUMMARY muscle wasting, the Cancer Cachexia Program at Ohio State University has begun a TR:TREATMENT_SUMMARY Pancreatic Cancer Cachexia Tissue Bank. To date, over 130 patients undergoing TR:TREATMENT_SUMMARY attempted resection for pancreatic cancer or other abdominal surgeries have TR:TREATMENT_SUMMARY donated muscle and blood to our bank. A unique aspect of our tissue bank is our TR:TREATMENT_SUMMARY focus on patients eligible for resection. In contrast to other studies using TR:TREATMENT_SUMMARY patients with late-stage disease, our patients are not end-stage, as they are TR:TREATMENT_SUMMARY considered healthy enough to undergo a major operation. " #SAMPLEPREP SP:SAMPLEPREP_SUMMARY TCA concentrations using serum #CHROMATOGRAPHY CH:CHROMATOGRAPHY_TYPE GC CH:INSTRUMENT_NAME Agilent 7890B CH:COLUMN_NAME Agilent HP5-MS (30m × 0.25mm, 0.25 um) #ANALYSIS AN:ANALYSIS_TYPE MS #MS MS:MS_COMMENTS - MS:INSTRUMENT_NAME Agilent 5977A MS:INSTRUMENT_TYPE Single quadrupole MS:MS_TYPE EI MS:ION_MODE POSITIVE #MS_METABOLITE_DATA MS_METABOLITE_DATA:UNITS uM MS_METABOLITE_DATA_START Samples Sample # 1 Sample # 2 Sample # 3 Sample # 4 Sample # 5 Sample # 6 Sample # 7 Sample # 8 Sample # 9 Sample # 10 Sample # 11 Sample # 12 Sample # 13 Sample # 14 Sample # 15 Sample # 16 Sample # 17 Sample # 18 Sample # 19 Sample # 20 Sample # 21 Sample # 22 Sample # 23 Sample # 24 Sample # 25 Sample # 26 Sample # 27 Sample # 28 Sample # 29 Sample # 30 Factors Grouping:Weight Losing | Gender:Female Grouping:Control | Gender:Male Grouping:Control | Gender:Female Grouping:Control | Gender:Female Grouping:Weight Losing | Gender:Male Grouping:Weight Losing | Gender:Male Grouping:Control | Gender:Female Grouping:Weight Stable | Gender:Male Grouping:Control | Gender:Female Grouping:Control | Gender:Male Grouping:Weight Stable | Gender:Male Grouping:Weight Stable | Gender:Male Grouping:Weight Losing | Gender:Male Grouping:Weight Losing | Gender:Male Grouping:Control | Gender:Male Grouping:Weight Stable | Gender:Female Grouping:Weight Stable | Gender:Female Grouping:Control | Gender:Female Grouping:Weight Stable | Gender:Female Grouping:Control | Gender:Male Grouping:Weight Losing | Gender:Female Grouping:Weight Losing | Gender:Female Grouping:Weight Stable | Gender:Male Grouping:Weight Stable | Gender:Female Grouping:Weight Stable | Gender:Female Grouping:Weight Losing | Gender:Female Grouping:Control | Gender:Male Grouping:Weight Stable | Gender:Male Grouping:Weight Losing | Gender:Female Grouping:Weight Losing | Gender:Male Lactate 2097 2424 3012 2234 2285 1796 1749 2520 3790 1971 2240 2208 2485 1530 1114 915 1811 4409 2267 2269 2737 997 2544 2655 2486 1843 2397 2970 1925 1637 Succinate 3.66 6.19 6.99 4.53 6.22 3.70 3.07 2.53 5.84 3.43 4.77 3.76 7.63 2.93 2.09 5.24 3.38 4.79 15.96 4.52 2.81 3.42 18.07 4.32 3.76 3.25 9.40 4.36 4.15 4.75 Fumarate 4.91 4.98 6.41 3.43 2.78 3.04 2.86 2.00 3.59 2.86 1.72 2.67 4.05 2.14 1.77 2.80 1.88 4.13 2.17 3.07 1.91 1.54 2.49 2.08 1.75 1.54 2.38 1.98 3.23 3.19 Oxaloacetate 0.05 0.04 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.08 0.04 0.06 0.08 0.03 0.03 0.05 0.03 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.05 0.06 0.02 0.04 0.03 0.03 Ketoglutarate 6.65 8.91 10.29 9.76 15.25 8.02 8.39 11.77 9.54 8.00 6.04 8.81 27.59 8.74 4.61 9.19 7.90 13.02 8.58 13.96 11.11 6.34 9.11 8.72 21.85 8.04 8.05 11.07 10.76 14.32 Malate 4.76 4.93 6.48 6.45 3.75 4.69 3.72 3.48 5.84 5.18 4.23 5.54 7.93 4.07 2.80 4.10 2.96 5.24 6.39 7.21 4.81 2.79 4.03 4.26 4.07 3.18 4.09 5.57 7.83 7.74 Aspartate 3.86 2.08 8.63 4.21 4.14 4.37 4.50 4.70 6.00 7.41 9.55 8.28 4.37 4.14 3.72 4.04 3.30 6.14 6.25 4.82 5.04 5.86 6.31 7.96 5.15 4.96 3.03 5.37 4.11 3.75 2-Hydroxyglutarate 0.77 0.57 0.78 0.72 0.74 0.62 0.60 0.37 1.41 0.84 0.80 1.01 2.89 0.52 0.43 0.68 0.62 0.64 0.68 1.40 0.44 0.63 0.63 0.95 0.54 0.45 0.65 1.28 0.50 0.70 Glutamate 81.98 25.18 113.24 42.29 125.46 74.57 90.52 126.74 84.75 171.18 311.89 116.20 208.42 115.95 93.09 79.42 38.23 128.50 71.20 98.48 83.21 108.69 122.79 97.94 137.71 61.02 66.81 97.37 84.08 83.33 cis-Aconitic Acid 6.40 4.25 3.39 1.90 2.47 2.59 2.37 2.08 3.78 2.56 3.71 1.73 1.40 1.84 2.19 1.44 1.23 1.93 1.39 3.26 1.58 1.70 1.74 2.62 1.93 1.91 1.87 1.29 2.08 2.43 Citrate 107.93 125.08 114.79 85.51 106.73 131.59 110.37 70.70 125.36 106.32 67.45 83.16 91.18 83.95 64.45 93.86 101.01 104.94 152.36 104.13 98.91 102.63 91.92 78.64 83.93 102.94 121.79 110.09 107.06 77.84 Isocitrate 3.95 2.00 1.81 1.34 1.52 1.66 1.19 0.97 1.77 1.55 1.51 1.00 1.09 1.20 1.25 1.26 1.42 1.37 1.75 1.84 1.23 1.20 1.27 1.26 1.17 1.38 1.18 1.13 1.31 1.31 MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name Lactate Succinate Fumarate Oxaloacetate Ketoglutarate Malate Aspartate 2-Hydroxyglutarate Glutamate cis-Aconitic Acid Citrate Isocitrate METABOLITES_END #END