Abstract

Background

Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival (OS) benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.

Methods

Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and micro (mi)RNA profiles were associated with patients’ OS and progression-free survival.

Results

In the first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. In the second step, a mini-signature of 2 gene transcripts (HIF1A, CDKN1A) and 3 miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range, 10.6–20.8 mo).

Conclusions

The study provides evidence that a signature based on the expression of 5 biomarkers could help identify a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Although the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guide the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

中文翻译：

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瑞格非尼治疗胶质母细胞瘤患者延长生存期的分子标记

抽象的

背景

胶质母细胞瘤（GBM）患者的预后极差。最近的REGOMA试验表明，复发性GBM患者使用regorafenib的总体生存（OS）获益。考虑到GBM的极端遗传异质性，我们旨在鉴定可预测对该药物反应不同的分子生物标记。

方法

从参加REGOMA试验的患者的肿瘤样本中提取总RNA。全基因组转录组和微小（mi）RNA谱与患者的OS和无进展生存期相关。

结果

第一步是一组11个基因转录本（HIF1A，CTSK，SLC2A1，KLHL12，CDKN1A，CA12，WDR1，CD53，CBR4，NIFK-AS1，RAB30-DT）和10个miRNA（miR-93-5p，miR- 203a-3p，miR-17-5p，let-7c-3p，miR-101-3p，miR-3607-3p，miR-6516-3p，miR-301a-3p，miR-23b-3p，miR-222-通过比较雷戈非尼和洛莫司汀组之间的生存期来过滤3p）。在第二步中，由2个基因转录物（HIF1A，CDKN1A）和3个miRNA（miR-3607-3p，miR-301a-3p，miR-93-5p）组成的微型签名确定了雷戈非尼术后存活时间延长的患者亚组管理（中位操作系统范围，10.6–20.8 mo）。

结论

这项研究提供了证据，表明基于5种生物标志物的表达的签名可以帮助鉴定使用雷戈非尼治疗时表现出惊人生存优势的GBM患者亚组。尽管必须在更大的复制人群中证实所提出的结果，但该研究强调了潜在的生物标志物选择，可帮助指导瑞戈非尼和其他治疗GBM复发患者的临床决策。