文章：

多激酶抑制剂治疗胶质母细胞瘤：评估瑞戈非尼的合理性

Multikinase Treatment of Glioblastoma: Evaluating the Rationale for Regorafenib

原文发布日期：23 January 2025

DOI: 10.3390/cancers17030375

类型: Article

开放获取: 是

英文摘要：

We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib’s binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood–brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug’s ability to reach brain tumors at adequate concentrations.

摘要翻译： 

本研究探讨了使用瑞戈非尼治疗胶质母细胞瘤（GBM）的理论依据。我们在103例新诊断的GBM患者中，评估了46个编码可能被瑞戈非尼或其代谢物靶向的蛋白激酶（PKs）基因的突变、拷贝数变异（CNVs）、融合及过表达情况，并进行了功能富集分析以评估其在血管生成中的潜在作用。我们分析了瑞戈非尼对这46种PKs的结合抑制活性及靶点亲和力，重点关注了在临床可达到浓度下被瑞戈非尼抑制的18个基因子集，以及参与血管生成的19个基因。假定的致癌性改变被定义为致癌/可能致癌的突变、致癌性融合、CNVs > 5和/或基因过表达。瑞戈非尼并未靶向全部46种PKs。在46个基因集合中，40个基因（86.9%）和73例患者（70.8%）在编码可靶向PKs的基因中至少存在一种改变，但仅34例患者（33%）存在假定的致癌性改变。在18个基因集合中，18个基因（100%）和48例患者（46.6%）存在改变，但仅26例患者（25.2%）检测到假定的致癌性改变。30例患者（29.1%）在18个基因集合和/或血管生成相关基因中存在致癌性改变。约33%的患者在46个潜在靶点中的任意一个存在致癌性改变。此外，由于瑞戈非尼对血脑屏障的穿透性较差，其剂量使用可能未达最优，这可能会降低有效靶向某些PKs的可能性。未来使用多靶点药物必须基于对靶点存在情况、有效抑制程度以及药物在脑肿瘤中达到足够浓度的能力的深入理解来指导。

原文链接：

Multikinase Treatment of Glioblastoma: Evaluating the Rationale for Regorafenib