Pladevall-Morera David, Castejón-Griñán María, Aguilera Paula, Gaardahl Karina, Ingham Andreas, Brosnan-Cashman Jacqueline A, Meeker Alan K, Lopez-Contreras Andres J
Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, Universidad Pablo de Olavide, 41013 Seville, Spain.
Cancers (Basel). 2022 Mar 31;14(7):1790. doi: 10.3390/cancers14071790.
High-grade glioma, including anaplastic astrocytoma and glioblastoma (GBM) patients, have a poor prognosis due to the lack of effective treatments. Therefore, the development of new therapeutic strategies to treat these gliomas is urgently required. Given that high-grade gliomas frequently harbor mutations in the SNF2 family chromatin remodeler , we performed a screen to identify FDA-approved drugs that are toxic to ATRX-deficient cells. Our findings reveal that multi-targeted receptor tyrosine kinase (RTK) and platelet-derived growth factor receptor (PDGFR) inhibitors cause higher cellular toxicity in high-grade glioma ATRX-deficient cells. Furthermore, we demonstrate that a combinatorial treatment of RTKi with temozolomide (TMZ)-the current standard of care treatment for GBM patients-causes pronounced toxicity in ATRX-deficient high-grade glioma cells. Our findings suggest that combinatorial treatments with TMZ and RTKi may increase the therapeutic window of opportunity in patients who suffer high-grade gliomas with mutations. Thus, we recommend incorporating the status into the analyses of clinical trials with RTKi and PDGFRi.
高级别胶质瘤，包括间变性星形细胞瘤和胶质母细胞瘤（GBM）患者，由于缺乏有效的治疗方法，预后较差。因此，迫切需要开发新的治疗策略来治疗这些胶质瘤。鉴于高级别胶质瘤经常在SNF2家族染色质重塑因子中存在突变，我们进行了一项筛选，以确定对ATRX缺陷细胞有毒性的FDA批准药物。我们的研究结果表明，多靶点受体酪氨酸激酶（RTK）和血小板衍生生长因子受体（PDGFR）抑制剂在高级别胶质瘤ATRX缺陷细胞中引起更高的细胞毒性。此外，我们证明，RTKi与替莫唑胺（TMZ）（GBM患者目前的标准护理治疗药物）联合治疗在ATRX缺陷的高级别胶质瘤细胞中引起明显的毒性。我们的研究结果表明，TMZ和RTKi联合治疗可能会增加患有突变的高级别胶质瘤患者的治疗机会窗口。因此，我们建议将 状态纳入RTKi和PDGFRi临床试验分析中。
