Combination of palbociclib and radiotherapy for glioblastoma.
Combination of palbociclib and radiotherapy for glioblastoma.
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DOI：
10.1038/cddiscovery.2017.33
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发表时间：
2017
影响因子：
7
通讯作者：
McDonald KL
中科院分区：
文献类型：
--
作者：
Whittaker S;Madani D;Joshi S;Chung SA;Johns T;Day B;Khasraw M;McDonald KL
细胞周期蛋白依赖性激酶抑制剂帕博西尼 (palbociclib) 在乳腺癌患者中显示出令人瞩目的疗效。几项胶质母细胞瘤 (GBM) 的临床前研究也表明 Palbociclib 有效。在这项研究中，我们研究了哌柏西利联合放射疗法 (RT) 治疗 GBM。我们在四种患者来源的细胞系（PDCL；RB1 保留；CDKN2A 丢失）上测试了 Palbociclib（有或没有 RT）。我们在体外使用流式细胞术研究了治疗对细胞周期和细胞凋亡的影响。 Balb/c 裸鼠颅内注射 PDCL、GBM-L1，并口服 Palbociclib（联合或不联合 RT）治疗。测量了总体生存率。 Palbociclib 治疗导致处于 G1 细胞周期期的细胞百分比显着增加。通过膜联蛋白 V 测量，诱导细胞凋亡。 Palbociclib 与 RT 联合发挥协同作用，显着阻碍集落形成。与对照小鼠相比，口服哌柏西利的小鼠没有表现出任何显着的生存优势，但与 RT 联合治疗时，观察到了 8 天的生存优势。我们的结果支持使用哌柏西利作为放疗的辅助治疗，并有必要转化为临床。
The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis using flow cytometry, in vitro. Balb/c nude mice were intracranially injected with the PDCL, GBM-L1 and treated orally with palbociclib (with and without RT). Overall survival was measured. Palbociclib treatment resulted in a significant increase in the percentage of cells in the G1 cell cycle phase. Apoptotic cell death, measured by Annexin V was induced. Palbociclib combined with RT acted synergistically with the significant impediment of colony formation. The oral treatment of mice with palbociclib did not show any significant survival advantage when compared to control mice, however when combined with RT, a survival advantage of 8 days was observed. Our results support the use of palbociclib as an adjuvant treatment to RT and warrant translation to the clinic.