Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA575912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10233400_1.fastq.gz | Fastqsanger.gz | |||
| SRR10233400_2.fastq.gz | Fastqsanger.gz | |||
| SRR10233401_1.fastq.gz | Fastqsanger.gz | |||
| SRR10233401_2.fastq.gz | Fastqsanger.gz | |||
| SRR10233402_1.fastq.gz | Fastqsanger.gz |
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Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.
2019-11-20 | GSE138464 | GEO
Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated ?-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachexia.
| S-SCDT-EMM-2018-09910 | biostudies-other
Project description:No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated ?-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.
| S-EPMC7005646 | biostudies-literature
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:Cachexia is a systemic metabolic syndrome characterized by loss of fat and skeletal muscle mass in chronic wasting diseases such as cancer. The regulation of cellular protein synthesis in response to workload in skeletal muscle is generally blunted in cancer cachexia; however, the precise molecular regulation is largely unknown. In this study, to examine the molecular mechanism of skeletal muscle protein metabolism in cancer cachexia, we analyzed comprehensive gene expression in skeletal muscle using microarrays. CD2F1 mice (male, 7 weeks old) were subcutaneously transplanted (1*10^6 cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Functional overload of the plantaris muscle by synergist ablation was performed at the 2nd week, and the plantaris muscle was sampled at the 4th week of cancer transplantation. The hypertrophy of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mTOR signaling) associated with compensatory overload was significantly suppressed with the cancer cachexia. Gene expression profiling and pathway analysis by microarray showed that resistance to muscle protein synthesis associated with cancer cachexia was induced by downregulation of insulin-like growth factor-1. These observations show that cancer cachexia induces resistance to muscle protein synthesis, which could be a potential factor inhibiting the adaptation of skeletal muscle growth to physical exercise.
2021-10-15 | GSE185934 | GEO
Project description:Anabolic resistance of skeletal muscle in cancer cachexia is caused by impaired IGF1 expression to mechanical loading
| PRJNA771389 | ENA
Project description:Purpose: We assessed the anti-cachectic activity of the novel HDAC inhibitor AR-42 in murine models of cancer cachexia. Methods: Effects on classic features of cachexia, including decreased body weight, skeletal muscle and adipose tissue mass, muscle fiber cross-sectional area, and muscle strength, and increased intramuscular mRNA expression of E3 ligases Atrogin-1/MAFbx and MuRF1 were examined. Metabolomic analysis, whole transcriptome shotgun sequencing (RNA-seq) analysis, and cytokine profiling were used to compare metabolic phenotype and mRNA expression profiles in muscle, and cytokine production in serum, respectively, in AR-42- and vehicle-treated tumor-bearing and tumor-free control mice. Results: Orally administered AR-42 suppressed cancer cachexia in the C-26 colon adenocarcinoma model. This anti-cachectic effect, also confirmed in Lewis lung carcinoma-bearing mice, was not observed after treatment with other HDAC inhibitors (vorinostat, romidepsin). Cytokine profiling and RNA-seq analyses revealed effects of AR-42 on tumor-induced changes in inflammatory cytokine production and multiple transcriptional programs in muscle, including the inhibition of multiple pro-cachexia drivers, such as IL-6 and its receptor IL-6ra, leukemia inhibitory factor, Foxo1, Atrogin-1, MuRF1, adipose triglyceride lipase, uncoupling protein 3, and myocyte enhancer factor 2c. Metabolomic analysis indicated the reprogramming of skeletal muscle metabolism, including reduced glycolysis and glycogen synthesis and increased protein degradation, which was restored by AR-42 to a state characteristic of tumor-free mice. Conclusions: These findings support further investigation of AR-42 as part of a comprehensive therapeutic strategy for cancer cachexia.
2015-03-13 | GSE65936 | GEO
Project description:Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia associates with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models that fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA, that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology to cachectic patients. We envision the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
2019-08-06 | GSE133524 | GEO
Project description:Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia associates with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models that fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA, that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology to cachectic patients. We envision the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
2019-08-06 | GSE133523 | GEO
Project description:Pancreatic cancer is characterized by a high frequency of cachexia, pain and neural invasion (N-inv). Neural damage is occurred by N-inv and modulates pain and muscle atrophy via the activation of astrocyte in the connected spine. The activated astrocyte by N-inv, thus, may affect cachexia in pancreatic cancer. Clinical studies in patients and autopsy cases with pancreatic cancer have revealed that N-inv is related to cachexia and astrocytic activation. We established a novel murine model of cancer cachexia using N-inv of human pancreatic cancer cells. Mice with N-inv showed a loss of body weight, skeletal muscle, and fat mass without appetite loss, which are compatible with an animal model of cancer cachexia. Activation of astrocytes in the spinal cord connected with N-inv was observed in our model. Experimental cachexia was suppressed by disrupting neural routes or inhibiting the activation of astrocytes. These data provide the first evidence that N-inv induces cachexia via astrocytic activation of neural route in pancreatic cancer. We produced neural invasion (N-inv) model using intraneural injection of Capan-1 cells to left sciatic nerve of male SCID mouse. For controls, subcutaneous model (SC) and PBS model were produced. Microarray analysis was performed using the first lumbar cord (L1) from PBS, SC, and N-inv mice at 6 w (n = 2 each).
2011-12-07 | E-GEOD-34189 | biostudies-arrayexpress