Study of GTx-024 on Muscle Wasting (Cachexia) Cancer.
Ontology highlight
ABSTRACT:
DISEASE(S): Muscular Atrophy,Colorectal Cancer,Non-small Cell Lung Cancer,Cachexia,Wasting Syndrome
PROVIDER: 2039568 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Cancer cachexia is a multifactorial wasting syndrome affecting body and lean tissue mass that is often exacerbated by anticancer chemotherapy. In this study, we used a mouse model of acute myeloid leukemia chemotherapy induction regimen (CIR) comprising daunorubicin and cytarabine to investigate the molecular mechanisms underlying cachexia. Quantitative tandem mass tag (TMT) based proteomics was performed on skeletal muscle (quadriceps) to uncover biomarkers and pathways associated with chemotherapy induced muscle wasting. Our findings demonstrate that the AML CIR induced an acute cachexic phenotype characterized by approximately 10 percent body and lean mass loss and 20 percent muscle fibre atrophy. Through deep proteome profiling, two potential biomarkers—haptoglobin (Hp) and glutamine synthetase (Glul)—were identified. Haptoglobin in particular was responsive to cachexia severity, recovery, and exacerbation via exercise, indicating its potential as a conditionally sensitive biomarker of muscle wasting. Pathway analysis revealed upregulation of mitochondrial metabolism including branched chain amino acid catabolism and mitochondrial uncoupling proteins (Ucp1 and Ucp3), suggesting hypermetabolism as a key driver of the phenotype. These data support the use of skeletal muscle proteomics in characterizing chemotherapy induced cachexia and identifying sensitive muscle specific biomarkers for future translational and therapeutic studies.
2025-06-16 | PXD063910 | Pride
Project description:Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that Forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal muscle clock in response to cancer, that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal muscle circadian transcriptome towards pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal muscle circadian transcriptome which may contribute to muscle wasting and the development of cachexia.
2025-05-11 | GSE273879 | GEO
Project description:Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that Forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal muscle clock in response to cancer, that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal muscle circadian transcriptome towards pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal muscle circadian transcriptome which may contribute to muscle wasting and the development of cachexia.
2025-05-11 | GSE273712 | GEO
Project description:Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that Forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal muscle clock in response to cancer, that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal muscle circadian transcriptome towards pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal muscle circadian transcriptome which may contribute to muscle wasting and the development of cachexia.
2025-05-11 | GSE273878 | GEO
Project description:Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass, and is associated with poor clinical outcome, decreased survival and negative impact on tumor therapy. Various lung tumor-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer cachexia (OLCC) mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia. Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumor-bearing (OLCC) group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumor growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized and skeletal muscles of the lower hind limbs were collected forRNA sequencing. RNA sequencing was performed on the Illumina NovasSeq 6000.
2023-04-03 | E-MTAB-12780 | biostudies-arrayexpress
Project description:The aim of the study is to identify genes and pathways associated with muscle and adipose wasting in PDAC cachexia. Muscle and adipose were collected from same individuals to study the concurrent muscle and adipose wasting.
2021-04-01 | GSE133979 | GEO
Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.
2021-07-14 | GSE173250 | GEO
Project description:Background
Cancer Cachexia (CC) is a multi-factorial process characterized by progressive weight loss, muscle mass and fat tissue wasting, and adversely affecting their quality of life and survival in patients with advanced stage of cancer.
Megestrol acetate (MA), which can help maintain body weight in advanced cancer patients, has not been proven to be effective in improving quality of life or lean body mass. Furthermore, its use is often limited due to various adverse event such as Cushing syndrome, adrenal insufficiency, or thromboembolic risk.
CC has a complex and multi-factorial pathophysiology, and there is no established standard treatment.
Hypothesis CC is irreversible once it occurs and is also difficult to suppress its progression with any single treatment modality.
The investigators hypothesized that a multi-modal intervention comprised of anti-inflammation, omega-3-fatty acids, oral nutritional supplement with counselling by nutritionist, physical exercise, psychiatric intervention as well as Bojungikki-tang which mediates immune-modulation and reverse both of chronic inflammation and wasting condition as a complementary and alternative medicine (CAM) could prevent the development of CC or improve the CC in advanced cancer patients during chemotherapy compared to those who received usual supportive.
| 2379147 | ecrin-mdr-crc
Project description:Background: Cancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease, so that effective therapies can be developed. Almost all pre-clinical studies evaluating skeletal muscle’s response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice. Methods: To create the four cohorts of PDX mice evaluated in this study, tumors resected from four pancreatic ductal adenocarcinoma (PDAC) patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results: Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumor-burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA revealed key differences between their transcriptomes in response to cancer as well. Indeed, upregulated genes in the diaphragm were enriched for extracellular matrix (ECM) protein-encoding genes and genes related to the inflammatory response, and downregulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed upregulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis and enrichment of downregulated genes encoding ECM proteins. Conclusions: These data suggest that distinct biological processes account for wasting in different skeletal muscles in response to the same tumor burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.
2020-03-10 | GSE137979 | GEO
Project description:Background: Cancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease, so that effective therapies can be developed. Almost all pre-clinical studies evaluating skeletal muscle’s response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice. Methods: To create the four cohorts of PDX mice evaluated in this study, tumors resected from four pancreatic ductal adenocarcinoma (PDAC) patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results: Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumor-burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA revealed key differences between their transcriptomes in response to cancer as well. Indeed, upregulated genes in the diaphragm were enriched for extracellular matrix (ECM) protein-encoding genes and genes related to the inflammatory response, and downregulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed upregulation of canonical atrophy-associated pathways such as ubiquitin-mediated protein degradation and apoptosis and enrichment of downregulated genes encoding ECM proteins. Conclusions: These data suggest that distinct biological processes account for wasting in different skeletal muscles in response to the same tumor burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.
2020-03-10 | GSE137960 | GEO