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Selpercatinib mitigates cancer cachexia independent of anti-tumor activity

ABSTRACT: Selpercatinib mitigates cancer cachexia independent of anti-tumor activity

PROVIDER: PRJNA1130906 | ENA |

REPOSITORIES: ENA

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			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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Selpercatinib mitigates cancer cachexia independent of anti-tumor activity

Project description:We determine whether the RET protein tyrosine kinase inhibitor selpercatinib alleviates skeletal muscle atrophy in the HT1080 tumor model in mice.

2025-05-09 | GSE271312 | GEO

Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

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

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

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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Impaired cAMP/CREB1 signaling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia [ChIP-seq]

Project description:Skeletal muscle wasting is a hallmark of cachexia, a cancer-associated syndrome that severely affects patients’ quality of life. Emerging evidence indicates that at early stages of cachexia a large transcriptional network of genes involved in mitochondrial biogenesis, dynamics, and function is down-regulated in skeletal muscle, thus leading to mitochondrial dysfunction and muscle wasting. Here, by exploiting in vivo and in vitro cachexia models, we report that i) tumor-induced impairment of cAMP/CREB1 signaling in skeletal muscle contributes to the downregulation of the transcriptional network sustaining mitochondrial function; ii) the cAMP-hydrolyzing phosphodiesterases 4D (PDE4D), whose transcript variants are deregulated in cachectic muscle, mediates tumor-induced cAMP signaling impairment in vitro. iii) boosting cAMP signaling by targeting PDE4 in vivo rescues mitochondrial-related gene expression, mitochondrial dysfunction, and mitigates muscle wasting. Collectively, we identified tumor-induced impairment of cAMP/CREB1 signaling as a driver of skeletal muscle mitochondrial dysfunction occurring during cancer cachexia.

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GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia

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.

2023-07-02 | GSE235940 | GEO

The evaluation of exosomal miRNA biomarkers for cachexia

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.

2024-12-23 | GSE221666 | GEO

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