Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
Clin Cancer Res. 2022 Sep 1;28(17):3890-3901. doi: 10.1158/1078-0432.CCR-22-0569.
SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib ± selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction.
The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells.
Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP1 were identified as candidate biomarkers at baseline from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23 × 10-5, 2.22 × 10-5, and 2.23 × 10-5, respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34 × 10-5 and 7.98 × 10-4, respectively. HCC tumor was the likely origin of circulating EVs.
In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.
SORAMIC 是一项针对接受索拉非尼±选择性内部放射治疗（SIRT）的晚期肝细胞癌（HCC）患者的随机对照试验。我们研究了基于细胞外囊泡（EV）的蛋白质组学在治疗反应预测中的价值。
分析人群包括 25 名接受 SIRT+索拉非尼和 20 名接受索拉非尼单药治疗的患者。根据 AFP 和影像学或总生存期的变化，将患者分为应答者和无应答者。通过 LC/MS 对血浆 EV 进行蛋白质组学分析，然后进行生物信息学分析。通过生存和接受者操作特征分析以及 bootstrap 内部采样验证，对候选 EV 蛋白的临床相关性进行验证。通过对肝和肿瘤组织的免疫组织化学染色以及血细胞的转录组学研究，探索循环 EV 的来源。
蛋白质组学分析鉴定出在接受 SIRT+索拉非尼和单独接受索拉非尼治疗的应答者和无应答者的血浆 EV 中，有 56 种和 27 种 EV 蛋白存在差异表达。从 13 名对 SIRT+索拉非尼有反应的患者中，基线时高 EV-GPX3/ACTR3 和低 EV-ARHGAP1 被确定为候选生物标志物，其 AUC 为 1，bootstrap P 值分别为 2.23×10-5、2.22×10-5 和 2.23×10-5。这些患者在联合治疗后 6 至 9 周时，EV-VPS13A 和 EV-KALRN 的丰度降低，AUC 和 bootstrap P 值均有显著意义。相反，低 GPX3 和高 ARHGAP1 对索拉非尼单药治疗的反应更好，AUC 分别为 0.9697 和 0.9192，bootstrap P 值分别为 8.34×10-5 和 7.98×10-4。HCC 肿瘤可能是循环 EV 的来源。
在这项探索性研究中，基于 EV 的蛋白质组学预测了代谢起源的晚期 HCC 患者对 SIRT+索拉非尼和索拉非尼单药治疗的反应。
