Glioblastoma is the most common primary malignant tumor in the brain and has a dismal prognosis despite patients accepting standard therapies. Alternation of genes and deregulation of proteins, such as receptor tyrosine kinase, PI3K/Akt, PKC, Ras/Raf/MEK, histone deacetylases, poly (ADP-ribose) polymerase (PARP), CDK4/6, branched-chain amino acid transaminase 1 (BCAT1), and Isocitrate dehydrogenase (IDH), play pivotal roles in the pathogenesis and progression of glioma. Simultaneously, the abnormalities change the cellular biological behavior and microenvironment of tumor cells. The differences between tumor cells and normal tissue become the vulnerability of tumor, which can be taken advantage of using targeted therapies. Small molecule inhibitors, as an important part of modern treatment for cancers, have shown significant efficacy in hematologic cancers and some solid tumors. To date, in glioblastoma, there have been more than 200 clinical trials completed or ongoing in which trial designers used small molecules as monotherapy or combination regimens to correct the abnormalities. In this review, we summarize the dysfunctional molecular mechanisms and highlight the outcomes of relevant clinical trials associated with small-molecule targeted therapies. Based on the outcomes, the main findings were that small-molecule inhibitors did not bring more benefit to newly diagnosed glioblastoma, but the clinical studies involving progressive glioblastoma usually claimed “noninferiority” compared with historical results. However, as to the clinical inferiority trial, similar dosing regimens should be avoided in future clinical trials.

胶质母细胞瘤是大脑中最常见的原发性恶性肿瘤，尽管患者接受标准治疗，但预后不佳。基因改变和蛋白质失调，例如受体酪氨酸激酶、PI3K/Akt、PKC、Ras/Raf/MEK、组蛋白脱乙酰酶、聚（ADP-核糖）聚合酶 (PARP)、CDK4/6、支链氨基酸转氨酶1 (BCAT1) 和异柠檬酸脱氢酶 (IDH) 在胶质瘤的发病机制和进展中起关键作用。同时，这些异常改变了肿瘤细胞的细胞生物学行为和微环境。肿瘤细胞和正常组织之间的差异成为肿瘤的脆弱性，可以利用靶向治疗。小分子抑制剂作为现代癌症治疗的重要组成部分，在血液系统癌症和一些实体瘤中显示出显着疗效。迄今为止，在胶质母细胞瘤中，已经完成或正在进行 200 多项临床试验，其中试验设计者使用小分子作为单一疗法或联合疗法来纠正异常。在这篇综述中，我们总结了功能失调的分子机制，并强调了与小分子靶向治疗相关的相关临床试验的结果。基于结果，主要发现是小分子抑制剂并未给新诊断的胶质母细胞瘤带来更多益处，但涉及进行性胶质母细胞瘤的临床研究通常声称与历史结果相比具有“非劣效性”。然而，对于临床劣效性试验，在未来的临床试验中应避免类似的给药方案。