Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy.
Using a preclinical mouse model of high-grade astrocytoma to optimize p53 restoration therapy.
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使用高级别星形细胞瘤临床前小鼠模型来优化 p53 恢复疗法。
DOI：
10.1073/pnas.1219142110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Evan,GerardI
中科院分区：
文献类型：
--
作者：
Shchors,Ksenya;Persson,AndersI;Rostker,Fanya;Tihan,Tarik;Lyubynska,Natalya;Li,Nan;Swigart,LamornaBrown;Berger,MitchelS;Hanahan,Douglas;Weiss,WilliamA;Evan,GerardI
根据临床表现，胶质母细胞瘤（GBM）分为原发性和继发性类型。在大多数 GBM 中，蛋白质 53 (p53) 通路因独特的类型特异性机制而功能丧失。为了模拟人类神经胶质瘤发生，我们使用了与p53ERTAM背景交叉的GFAP-HRasV12小鼠模型，使得内源性p53的一个或两个拷贝被条件性p53ERTAM等位基因取代。通过分别给予或撤回 4-羟基他莫昔芬 (4-OHT)，p53ERTAM 蛋白可以在体内可逆地在野生型构象和失活构象之间切换。令人惊讶的是，在 GFAP-HRasV12;p53+/KI 小鼠中形成的神经胶质瘤通过突变 p19ARF/MDM2 同时保留野生型 p53 等位基因来废除 p53 通路。因此，此类肿瘤不受 p53ERTAM 等位基因恢复的影响。相比之下，GFAP-HRasV12;p53KI/KI小鼠中产生的神经胶质瘤在缺乏功能性p53的情况下发生。此类肿瘤保留了功能性 p19ARF/MDM2 信号通路，p53ERTAM 等位基因的恢复会触发 p53 肿瘤抑制活性。相应地，在人 GBM 培养物中，小分子 Prima-1 对突变 p53 正常化的生长抑制也需要 p14ARF/MDM2 功能。值得注意的是，p53 恢复在荷瘤 GFAP-HRasV12;p53KI/KI 动物中的抗肿瘤功效取决于 p53 恢复的持续时间和频率。因此，间歇性暴露于 p53ERTAM 活性可以减轻选择性压力，使 p19ARF/MDM2/p53 途径失活，作为抵抗手段，延长无进展生存期。我们的结果表明，通过类似地减少适应性抵抗，将野生型肿瘤抑制功能恢复到突变的、失活的 p53 蛋白上的药物间歇给药方案将比传统的长期给药更有效。
Based on clinical presentation, glioblastoma (GBM) is stratified into primary and secondary types. The protein 53 (p53) pathway is functionally incapacitated in most GBMs by distinctive type-specific mechanisms. To model human gliomagenesis, we used aGFAP-HRasV12mouse model crossed into thep53ERTAMbackground, such that either one or both copies of endogenous p53 is replaced by a conditionalp53ERTAMallele. The p53ERTAMprotein can be toggled reversibly in vivo between wild-type and inactive conformations by administration or withdrawal of 4-hydroxytamoxifen (4-OHT), respectively. Surprisingly, gliomas that develop inGFAP-HRasV12;p53+/KImice abrogate the p53 pathway by mutating p19ARF/MDM2 while retaining wild-type p53 allele. Consequently, such tumors are unaffected by restoration of theirp53ERTAMallele. By contrast, gliomas arising inGFAP-HRasV12;p53KI/KImice develop in the absence of functional p53. Such tumors retain a functional p19ARF/MDM2-signaling pathway, and restoration ofp53ERTAMallele triggers p53-tumor–suppressor activity. Congruently, growth inhibition upon normalization of mutant p53 by a small molecule, Prima-1, in human GBM cultures also requires p14ARF/MDM2 functionality. Notably, the antitumoral efficacy of p53 restoration in tumor-bearingGFAP-HRasV12;p53KI/KIanimals depends on the duration and frequency of p53 restoration. Thus, intermittent exposure to p53ERTAMactivity mitigated the selective pressure to inactivate the p19ARF/MDM2/p53 pathway as a means of resistance, extending progression-free survival. Our results suggest that intermittent dosing regimes of drugs that restore wild-type tumor-suppressor function onto mutant, inactive p53 proteins will prove to be more efficacious than traditional chronic dosing by similarly reducing adaptive resistance.