2. Academic Validation
  3. GDF-15 predicts epithelioid hemangioendothelioma aggressiveness and is down-regulated by sirolimus through ATF4/ATF5 suppression

GDF-15 predicts epithelioid hemangioendothelioma aggressiveness and is down-regulated by sirolimus through ATF4/ATF5 suppression

  • Clin Cancer Res. 2024 Sep 16. doi: 10.1158/1078-0432.CCR-23-3991.
Silvia Stacchiotti 1,  Silvia Martini 2,  Sandro Pasquali 2,  Anna M Frezza 1,  Alessia Beretta 2,  Stefano Percio 2,  Mara Lecchi 3,  Monica Tortoreto 1,  Marta Barisella 4,  Paola Collini 1,  Gian Paolo Dagrada 5,  Alessandra Merlini 6,  Paul H Huang 7,  Andrew Jenks 7,  Robin L Jones 8,  William D Tap 9,  Matilde Ingrosso 1,  Carlo Morosi 10,  Silvia Brich 10,  Claudia Giani 1,  Paolo Verderio 5,  Paolo G Casali 5,  Hugh Leonard 11,  Alessandro Gronchi 1,  Valentina Zuco 12,  Nadia Zaffaroni 13
Affiliations

Affiliations

  • 1 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • 2 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
  • 3 Fondazione IRCCS Istituto Tumori Milano, Milan, Italy.
  • 4 ASST Fatebenefratelli Sacco, Milan, Italy.
  • 5 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
  • 6 University of Turin, orbassano, torino, Italy.
  • 7 Institute of Cancer Research, London, United Kingdom.
  • 8 Royal Marsden Hospital, London, Chelsea, United Kingdom.
  • 9 Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • 10 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
  • 11 EHE Rare Cancer Charity UK, United Kingdom.
  • 12 Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
  • 13 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy, Italy.
PMID: 39283723 DOI: 10.1158/1078-0432.CCR-23-3991
Abstract

Purpose: Epithelioid hemangioendothelioma (EHE) poses a therapeutic challenge due to limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressiveness biomarkers. This study aimed at i) utilizing an EHE patient-derived xenograft (PDX) model 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 PDX model and corresponding cell line were established from an advanced EHE patient, 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 anti-tumor activity compared to 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.

Conclusion: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared to 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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