GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.
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ICR Authors
Authors
Stacchiotti, S
Martini, S
Pasquali, S
Frezza, AM
Beretta, A
Percio, S
Lecchi, M
Tortoreto, M
Barisella, M
Collini, P
Dagrada, GP
Merlini, A
Huang, PH
Jenks, A
Jones, RL
Tap, WD
Ingrosso, M
Morosi, C
Brich, S
Giani, C
Verderio, P
Casali, PG
Leonard, H
Gronchi, A
Zuco, V
Zaffaroni, N
Martini, S
Pasquali, S
Frezza, AM
Beretta, A
Percio, S
Lecchi, M
Tortoreto, M
Barisella, M
Collini, P
Dagrada, GP
Merlini, A
Huang, PH
Jenks, A
Jones, RL
Tap, WD
Ingrosso, M
Morosi, C
Brich, S
Giani, C
Verderio, P
Casali, PG
Leonard, H
Gronchi, A
Zuco, V
Zaffaroni, N
Document Type
Journal Article
Date
2024-11-15
Date Accepted
2024-09-12
Abstract
PURPOSE: Epithelioid 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 DESIGN: A 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. RESULTS: ELISA 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. CONCLUSIONS: This 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.
Citation
Clinical Cancer Research, 2024, 30 (22), pp. 5122 - 5137
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Mol and Systems Oncology
Sarcoma ClinTrials Jones
Sarcoma ClinTrials Jones