ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation.
ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation.
复制标题
DOI：
10.1158/1078-0432.ccr-12-3408
复制
发表时间：
2013-06-15
期刊：
影响因子：
--
通讯作者：
Valerie K
中科院分区：
文献类型：
--
作者：
Biddlestone-Thorpe L;Sajjad M;Rosenberg E;Beckta JM;Valerie NC;Tokarz M;Adams BR;Wagner AF;Khalil A;Gilfor D;Golding SE;Deb S;Temesi DG;Lau A;O'Connor MJ;Choe KS;Parada LF;Lim SK;Mukhopadhyay ND;Valerie K
多形性胶质母细胞瘤 (GBM) 是最致命的脑癌，中位生存期仅为 12-15 个月。目前的标准治疗包括手术和放化疗。 GBM 患者的生存率较低是由于肿瘤的侵袭性、无法清除所有肿瘤组织以及肿瘤固有的化学和放射抗性。 ATM（共济失调毛细血管扩张症 (A-T) 突变）是放射增敏 GBM 的绝佳靶点，因为它在调节 DNA 损伤反应和 p53 等细胞过程中发挥着关键作用。作为实现这一目标的第一步，我们最近证明新型 ATM 激酶抑制剂 KU-60019 可在体外减少人神经胶质瘤细胞的迁移、侵袭、生长和有效的放射增敏。使用 GBM 原位异种移植模型，我们现在证明 KU-60019 也是一种有效的体内放射增敏剂。表达用于监测肿瘤生长和扩散的报告基因的人神经胶质瘤细胞在颅内生长，并通过对流增强递送或渗透泵在肿瘤内施用 KU-60019。我们的结果表明，KU-60019 和辐射的联合作用使小鼠的存活率显着提高，是对照组小鼠的 2-3 倍。重要的是，我们发现具有突变 p53 的神经胶质瘤对 KU-60019 放射增敏比基因匹配的野生型神经胶质瘤更敏感。综上所述，我们的结果表明，ATM 激酶抑制剂可能是突变 p53 脑癌患者的有效放射增敏剂和辅助疗法。
Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12–15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of GBM patients is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. ATM, ataxia telangiectasia (A-T) mutated, is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, growth, and potently radiosensitized human glioma cells in vitro. Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intra-cranially, and KU-60019 was administered intra-tumorally by convection-enhanced delivery or osmotic pump. Our results demonstrate that the combined effect of KU-60019 and radiation significantly increased survival of mice 2–3 fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.