文章：

小分子抑制剂在胶质母细胞瘤治疗中的机遇与挑战：来自临床试验的经验教训

Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials

原文发布日期：29 August 2024

DOI: 10.3390/cancers16173021

类型: Article

开放获取: 是

英文摘要：

Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients.

摘要翻译： 

胶质母细胞瘤（GBM）是最常见的中枢神经系统肿瘤。尽管采用包括手术、放化疗及同步化疗在内的强化治疗方案，GBM患者的预后仍然较差，中位生存期仅为15个月。过去数十年来，针对参与肿瘤发生的特定基因的小分子抑制剂已开展大量临床试验。然而迄今为止这些试验均未取得成功，GBM的标准治疗方案自2005年以来仍未改变。本文综述了小分子抑制剂单药治疗、联合化疗或与其他小分子抑制剂联合应用的临床试验进展，重点探讨GBM中可能存在的耐药机制，包括肿瘤内与肿瘤间的异质性、旁路激活机制以及肿瘤微环境的影响。同时，我们强调联合用药策略如何有助于克服这些耐药机制，并提出通过优化试验设计提升研究效果的策略。总之，本综述旨在阐明针对小分子抑制剂的不同耐药机制，强调其在探索新型联合治疗方案、提高GBM患者总体生存率方面的重要意义。

原文链接：

Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical Trials