Department of Neurosurgery, Baylor College of Medicine , Houston, TX, USA.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
Expert Opin Ther Targets. 2020 Jul;24(7):605-614. doi: 10.1080/14728222.2020.1762568. Epub 2020 May 12.
The increasingly detailed genetic characterization of glioblastoma (GBM) has failed to translate into meaningful breakthroughs in treatment. This is likely to be attributed to molecular heterogeneity of GBM. However, the understanding of the tumor microenvironment in GBM has become more refined and has revealed a wealth of therapeutic targets that may enable the disruption of angiogenesis or immunosuppression.
This review discusses the selective targeting of tumor-intrinsic pathways, therapies that target the GBM tumor microenvironment and relevant preclinical studies and their limitations. Relevant literature was derived from a PubMed search encompassing studies from 1989 to 2020.
Despite appropriate target engagement, attempts to directly inhibit oncogenic pathways in GBM have yielded little success. This is likely attributed to the molecular heterogeneity of GBM and the presence of redundant signaling that allow for accumulation of adaptive mutations and development of drug resistance. Subsequently, there has been a shift toward therapies modulating the pro-angiogenic, immunosuppressive tumor microenvironment in GBM. The non-transformed cells in the microenvironment which includes endothelial cells, myeloid cells, and T cells, are presumably genetically stable, less susceptible to heterogeneity, and easier to target. This approach offers the highest potential for a therapeutic breakthrough in GBM.
对胶质母细胞瘤（GBM）的基因特征的研究越来越详细，但未能在治疗上取得显著突破。这很可能归因于 GBM 的分子异质性。然而，对 GBM 肿瘤微环境的理解已经变得更加精细，并揭示了大量治疗靶点，这些靶点可能能够破坏血管生成或免疫抑制。
本文讨论了肿瘤内在途径的选择性靶向、靶向 GBM 肿瘤微环境的疗法以及相关的临床前研究及其局限性。相关文献源自于 1989 年至 2020 年的 PubMed 搜索，包括了来自研究的文献。
尽管适当的靶向药物能够结合到靶点上，但直接抑制 GBM 中的致癌途径的尝试收效甚微。这可能归因于 GBM 的分子异质性以及存在冗余信号，这允许积累适应性突变并发展出药物抗性。随后，人们开始转向调节 GBM 中促血管生成、免疫抑制肿瘤微环境的疗法。微环境中的非转化细胞，包括内皮细胞、髓样细胞和 T 细胞，据推测具有遗传稳定性，不易发生异质性，且更容易成为治疗靶点。这种方法为 GBM 的治疗突破提供了最大的潜力。
