CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, IIIUC-Institute for Interdisciplinary Research, Coimbra, Portugal.
Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal Portugal.
Hum Mol Genet. 2021 Apr 26;30(3-4):160-171. doi: 10.1093/hmg/ddab011.
Despite the intense global efforts towards an effective treatment of glioblastoma (GB), current therapeutic options are unsatisfactory with a median survival time of 12-15 months after diagnosis, which has not improved significantly over more than a decade. The high tumoral heterogeneity confers resistance to therapies, which has hindered a successful clinical outcome, GB remaining among the deadliest cancers. A hallmark of GB is its high recurrence rate, which has been attributed to the presence of a small subpopulation of tumor cells called GB stem-like cells (GSC). In the present work, the efficacy of a multimodal strategy combining microRNA (miRNA) modulation with new generation multitargeted tyrosine kinase inhibitors (imatinib and axitinib) was investigated aiming at tackling this subpopulation of GB cells. MiR-128 and miR-302a were selected as attractive therapeutic candidates on the basis of previous findings reporting that reestablishment of their decreased expression levels in GSC resulted in cell differentiation, which could represent a possible strategy to sensitize GSC to chemotherapy. Our results show that overexpression of miR-128 or miR-302a induced GSC differentiation, which enhanced senescence mediated by axitinib treatment, thus further impairing GSC proliferation. We also provided evidence for the capacity of GSC to efficiently internalize functionalized stable nucleic acid lipid particles, previously developed and successfully applied in our laboratory to target GB. Taken together, our findings will be important in the future design of a GB-targeted multimodal miRNA-based gene therapy, combining overexpression of miR-128 or miR-302a with axitinib treatment, endowed with the ability to overcome drug resistance.
尽管全球在寻找有效治疗胶质母细胞瘤（GB）的方法方面付出了巨大努力，但目前的治疗选择仍不尽如人意，患者确诊后中位生存期仅为 12-15 个月，十多年来并未显著改善。肿瘤的高度异质性导致对治疗产生耐药性，从而阻碍了临床治疗效果，GB 仍然是最致命的癌症之一。GB 的一个标志是其高复发率，这归因于存在一小部分肿瘤细胞，称为 GB 干细胞样细胞（GSC）。在本研究中，我们采用了一种多模式策略，将 miRNA 调节与新一代多靶点酪氨酸激酶抑制剂（伊马替尼和阿昔替尼）相结合，旨在靶向治疗这种 GB 细胞亚群。基于先前的研究结果，选择 miR-128 和 miR-302a 作为有吸引力的治疗候选物，这些研究表明，重新建立它们在 GSC 中降低的表达水平可导致细胞分化，这可能是使 GSC 对化疗敏感的一种策略。我们的结果表明，miR-128 或 miR-302a 的过表达诱导 GSC 分化，这增强了阿昔替尼治疗介导的衰老，从而进一步抑制 GSC 的增殖。我们还提供了证据表明 GSC 能够有效地内化功能化的稳定核酸脂质颗粒，这些颗粒是我们实验室之前开发并成功应用于靶向 GB 的。综上所述，我们的研究结果对于未来设计靶向 GB 的多模式 miRNA 为基础的基因治疗具有重要意义，该治疗方法将结合 miR-128 或 miR-302a 的过表达与阿昔替尼治疗，从而具有克服耐药性的能力。
