The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.
The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.
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脑干神经胶质瘤是致命的儿童脑肿瘤，需要新的治疗方法。符合护理标准的治疗是放射治疗，但肿瘤在这种治疗后的某个时间点不可避免地进展。脑干神经胶质瘤的临床前研究中的一种治疗策略是抑制共济失调-毛细血管扩张突变激酶（ATM）的功能，ATM是细胞对放射治疗反应的主要调节因子。ATM抑制使一些肿瘤对放射治疗更敏感，但这可能取决于肿瘤的遗传组成。脑干神经胶质瘤的一个重要亚群在PTEN基因或相关基因中具有突变。在这里，我们开发了一个基因工程小鼠模型Pten突变的脑干胶质瘤。我们使用遗传工具来测试ATM失活是否可以增强Pten突变脑干胶质瘤模型中放射治疗的疗效。我们发现ATM失活并不能增强Pten突变脑干胶质瘤模型的放射治疗效果。这些结果表明，PTEN突变状态应考虑在设计纳入标准和相关研究，为未来的临床试验ATM抑制剂在脑干胶质瘤患者。弥漫性中线胶质瘤发生在脑干和其他中线脑结构中，并导致大部分儿童脑肿瘤死亡。放射治疗是最有效的治疗选择，但这些肿瘤最终会进展。抑制磷脂酰肌醇-3-激酶（PI 3 K）样激酶，共济失调-毛细血管扩张突变（ATM），协调细胞对辐射诱导的DNA损伤的反应，可能会提高放射治疗的疗效。脑干弥漫性中线神经胶质瘤含有肿瘤抑制基因PTEN的功能缺失突变，或磷酸肌醇-3-激酶（PI 3 K）途径的功能相似的改变，频率中等。在这里，我们试图确定ATM失活是否可以放射增敏由Pten丢失驱动的脑干胶质瘤的原代小鼠模型。利用Cre/loxP重组酶技术和RCAS/TVA逆转录病毒基因递送系统，建立Pten缺失驱动的小鼠脑干胶质瘤模型。我们发现，Pten无效脑干胶质瘤是相对放射敏感的基线。此外，我们发现，在肿瘤细胞中的Atm的删除并没有延长生存的小鼠轴承Pten空脑干胶质瘤后，局灶性脑照射。这些结果表征了一种新的PTEN突变脑干胶质瘤的原代小鼠模型，并为ATM缺失的放射增敏机制提供了见解，这可能会指导未来临床试验的设计。
Brainstem gliomas are deadly childhood brain tumors and new treatments are needed. The treatment meeting the standard of care is radiation therapy, but the tumors inevitably progress at some point after this treatment. One treatment strategy under preclinical investigation for brainstem gliomas is to inhibit the function of ataxia–telangiectasia mutated kinase (ATM), a master regulator of the cellular response to radiation therapy. ATM inhibition makes some tumors more sensitive to radiation therapy, but this may depend on the genetic makeup of the tumor. An important subset of brainstem gliomas harbor mutations in the PTEN gene or related genes. Here, we develop a genetically engineered mouse model of Pten-mutated brainstem glioma. We use genetic tools to test if ATM inactivation can enhance the efficacy of radiation therapy in this Pten-mutated brainstem glioma model. We find that ATM inactivation does not enhance the efficacy of radiation therapy for this model of Pten-mutated brainstem glioma. These findings indicate that PTEN mutational status should be considered in the design of inclusion criteria and correlative studies for future clinical trials of ATM inhibitors in brainstem glioma patients. Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.
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影响因子：
6.2
作者：
通讯作者：
--
DOI：
10.1016/0360-3016(95)00162-r
发表时间：
1995-09-30
影响因子：
7
作者：
LEE, SP;LEU, MY;WITHERS, HR
通讯作者：
WITHERS, HR
DOI：
10.1158/1541-7786.mcr-16-0389
发表时间：
2017-09
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Cordero FJ;Huang Z;Grenier C;He X;Hu G;McLendon RE;Murphy SK;Hashizume R;Becher OJ
通讯作者：
Becher OJ
影响因子：
15.9
作者：
Deland, Katherine;Starr, Bryce F.;Kirsch, David G.
通讯作者：
Kirsch, David G.
影响因子：
1.5
作者：
Lesche, R;Groszer, M;Wu, H
通讯作者：
Wu, H