Glioblastoma (GBM) is an incurable brain tumor with inevitable recurrence. This is in part due to a highly malignant cancer stem cell (CSC) subpopulation of tumor cells that is particularly resistant to conventional treatments, including radiotherapy. Here we show that CBL0137, a small molecule anti-cancer agent, sensitizes GBM CSCs to radiotherapy. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex to chromatin, resulting in cytotoxicity preferentially within tumor cells. We show that when combined with radiotherapy, CBL0137 inhibited GBM CSC growth and resulted in more DNA damage in the CSCs compared to irradiation or drug alone. Using an in vivo subcutaneous model, we showed that the frequency of GBM CSCs was reduced when tumors were pretreated with CBL0137 and then exposed to irradiation. Survival studies with orthotopic GBM models resulted in significantly extended survival for mice treated with combinatorial therapy. As GBM CSCs contribute to the inevitable recurrence in patients, targeting them is imperative. This work establishes a new treatment paradigm for GBM that sensitizes CSCs to irradiation and may ultimately reduce tumor recurrence.

胶质母细胞瘤（GBM）是一种无法治愈的脑肿瘤，不可避免地会复发。这部分是由于高度恶性的癌症干细胞 (CSC) 肿瘤细胞亚群对包括放射治疗在内的常规治疗特别有抵抗力。在这里，我们展示了 CBL0137，一种小分子抗癌剂，使 GBM CSCs 对放射治疗敏感。CBL0137 将 FACT（促进染色质转录）复合物与染色质隔离，从而优先在肿瘤细胞内产生细胞毒性。我们表明，与放疗或单独药物相比，CBL0137 与放疗联合使用可抑制 GBM CSC 生长，并导致 CSC 中更多的 DNA 损伤。使用体内在皮下模型中，我们发现当肿瘤用 CBL0137 预处理然后暴露于辐射时，GBM CSCs 的频率降低。用原位 GBM 模型进行的生存研究显着延长了接受联合治疗的小鼠的生存期。由于 GBM CSC 会导致患者不可避免地复发，因此针对它们势在必行。这项工作为 GBM 建立了一种新的治疗范式，使 CSC 对辐射敏感，并可能最终减少肿瘤复发。