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.

中文翻译：

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GDF-15 可预测上皮样血管内皮瘤的侵袭性，并通过 ATF4/ATF5 抑制被西罗莫司下调。


目的上皮样血管内皮瘤 （EHE） 是一种极其罕见的肉瘤，由于常规化疗在晚期病例中的疗效有限，因此带来了治疗挑战，需要探索新的治疗途径并识别新的侵袭性生物标志物。本研究旨在 （i） 利用 EHE 及其相关细胞系的患者来源的异种移植模型来评估西罗莫司的疗效，以及 （ii） 分析两个不同的患者队列以查明 EHE 侵袭性的循环生物标志物。实验设计 从晚期 EHE 患者中建立了患者来源的异种移植模型和相应的细胞系，证明在组织形态学、WWTR1：：CAMTA1 融合存在以及基因组和转录组学谱方面与原始肿瘤一致。采用两个独立的患者系列研究生长/分化因子 15 （GDF-15） 血清水平与 EHE 侵袭性之间的关联。结果 对 EHE 细胞培养基和携带 EHE 的小鼠血液进行 ELISA 分析，发现 EHE 细胞释放 GDF-15。与阿霉素相比，西罗莫司表现出显着更高的抗肿瘤活性，同时降低体内和体外 GDF-15 的表达/释放。这种降低归因于药物诱导的 4E-BP1 磷酸化/激活抑制以及随后 GDF-15 转录因子 ATF4 和 ATF5 的下调。来自两个独立患者系列的血样分析显示 GDF-15 与 EHE 侵袭性之间存在显著相关性。结论 本研究将 GDF-15 确定为 EHE 侵袭性的新型生物标志物，并强调了西罗莫司在我们的实验模型中与阿霉素相比的疗效优越。 观察到的西罗莫司对 GDF-15 释放的抑制表明其作为监测患者药物活性的生物标志物的潜力。