Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
J Exp Clin Cancer Res. 2021 Jul 12;40(1):228. doi: 10.1186/s13046-021-02031-4.
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs).
In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested.
Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo.
Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.
胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的原发性恶性脑肿瘤，其预后较差主要归因于复发和治疗耐药性。广泛研究表明，胶质母细胞瘤干细胞样细胞（GSCs）是具有干细胞样特性的肿瘤细胞亚群，负责肿瘤的维持和进展。此外，已经证明 GSCs 通过不同的机制有助于 GBM 相关的血管生成过程，包括向 GSC 衍生的内皮细胞（GdECs）的转分化。
为了确定 GBM 中可靶向的癌症相关途径，我们评估了 349 种化合物对 GSCs 和 GdECs 的作用，并选择 elesclomol（STA-4783）作为在测试的 GSC 和 GdEC 系中诱导细胞死亡最有效的药物。
Elesclomol 已被描述为一种有效的氧化应激诱导剂。对 GSCs 和 GdEC 对 elesclomol 反应的分子机制的深入研究证实，该化合物在 GSCs 和 GdECs 中均强烈诱导线粒体活性氧（ROS）增加，最终导致非凋亡性铜依赖性细胞死亡。此外，与 TMZ 单独治疗相比，在体外联合使用 elesclomol 和烷化剂替莫唑胺（TMZ）可增强细胞毒性。最后，我们使用小鼠脑异种移植的实验模型来测试 elesclomol 和 TMZ 的组合，并在体内证实了它们的疗效。
我们的结果支持进一步评估针对氧化应激的治疗方法，如 elesclomol，以满足 GBM 管理方面的高未满足医疗需求。
