ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Companion Diagnostics in Clinical Therapy: Current Applications and Future Directions.MedComm · 2026Review
- ATF5-Dependent GDF15 Expression Mediates Anesthesia-Induced Neuroprotection Against Stroke.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- EHE cell cultures are a platform for mechanistic and therapeutic investigation.Scientific reports · 2025Article
- Article
- Functional characteristics of fresh antitumor immune interferer GDF-15 in multiple cancers.Scientific reports · 2025Article
- Epithelioid Hemangioendothelioma: Treatment Landscape and Innovations for an Ultra-Rare Sarcoma.Current treatment options in oncology · 2025Review
- Exploring Treatments for Hepatic Epithelioid Hemangioendothelioma: A Subsegmental Bland Embolization Case Series With Review.Cancer control : journal of the Moffitt Cancer CenterReview
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Authors and funding
26 authors.
Funding
Abstract
purposeEpithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness. EXPERIMENTAL
designA patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.
resultsELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.
conclusionsThis study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.
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