Selpercatinib mitigates cancer cachexia independent of anti-tumor activity
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ABSTRACT:
PROVIDER: PRJNA1130906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29681671_1.fastq.gz | Fastqsanger.gz | |||
| SRR29681671_2.fastq.gz | Fastqsanger.gz | |||
| SRR29681672_1.fastq.gz | Fastqsanger.gz | |||
| SRR29681672_2.fastq.gz | Fastqsanger.gz | |||
| SRR29681673_1.fastq.gz | Fastqsanger.gz |
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Project description:We determine whether the RET protein tyrosine kinase inhibitor selpercatinib alleviates skeletal muscle atrophy in the HT1080 tumor model in mice.
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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.
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Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
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Project description:Cancer cachexia is a disorder characterized by both involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examined the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifested weight loss and muscle function impairments. With comprehensive assessments, our results demonstrated that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibited body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization were primarily attributed to increased caloric intake, while altered gene expressions in cachectic muscles were restored in both caloric intake-dependent and -independent manners. The findings implicate the potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.
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Project description:Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMPK complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an AAV-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth, and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof-of-concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development towards a novel, first-in-class approach against cancer cachexia.
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Project description:In order to screen miRNAs related to cachexia, we collected plasma from patients with gastric cancer cachexia or without cachexia, and extracted exosomes from plasma. Then, we analyzed the gene expression profile of 3 gastric cancer patients with cachexia and 2 gastric cancer patients with non cachexia.
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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.
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