Department of Neurosurgery, The Second Nanning People's Hospital, Nanning, Guangxi, 530031, China.
Department of Neurosurgery, The Third Nanning People's Hospital, Nanning, Guangxi, 530005, China.
J Mol Neurosci. 2024 May 10;74(2):52. doi: 10.1007/s12031-024-02201-x.
Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.
多形性胶质母细胞瘤（GBM）的治疗仍然具有挑战性。阐明谷氨酰胺代谢的调控机制可能为 GBM 治疗提供新的视角。本研究全面综合地解析了 GBM 中谷氨酰胺代谢图谱和异质性，以促进更有效的治疗选择的发展。本研究整合了来自大型 GBM 队列的转录组数据。通过共识聚类方法建立了基于谷氨酰胺代谢的分类，通过 LASSO 分析定义了分类器以区分分类。在每个聚类中，对预后、信号通路活性、肿瘤微环境以及对免疫检查点阻断（ICB）和小分子药物的反应进行了特征描述。提出了谷氨酰胺酶抑制剂 CB839 与青蒿琥酯（DHA）联合治疗的方案，并在 U251 和 U373 细胞中测量了对谷氨酰胺代谢、细胞凋亡、活性氧（ROS）和迁移的影响。我们发现，GBM 呈现出基于异质谷氨酰胺代谢的聚类，具有独特的生存结果、信号通路活性、肿瘤微环境以及对 ICB 和小分子化合物的反应。此外，该分类器可以准确地区分这两个聚类。引人注目的是，CB839 与 DHA 的联合治疗协同减弱了 GBM 细胞中的谷氨酰胺代谢，触发细胞凋亡和 ROS 积累，并损害了迁移能力，显示出优异的临床前疗效。总之，我们的研究结果揭示了 GBM 中谷氨酰胺代谢的异质性，并提出了一种使用 CB839 与 DHA 的联合创新治疗方案用于治疗这种恶性疾病。
