Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies
Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies
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DOI：
10.1093/neuonc/nov264
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发表时间：
2016-06-01
期刊：
影响因子：
15.9
通讯作者：
Chi, Susan N.
中科院分区：
文献类型：
--
作者：
Fruehwald, Michael C.;Biegel, Jaclyn A.;Chi, Susan N.
非典型的畸胎组/胸腺肿瘤（AT/RT）是6个月以下的儿童最常见的恶性中枢神经系统肿瘤。大多数AT/RTS表现出SMARCB1（INI1，SNF5，BAF47）的基因组改变，或者在较小程度上是开关/不可发酵染色质重塑复合物的SMARCA4（BRG1）。最近的转录和甲基化分析研究表明分子亚组的存在。因此，这些看似神秘的肿瘤的根源是与表观遗传调节有关的因素网络，尚未完全理解。尽管常规型化疗可能对某些患者具有显着的生存益处，但仍有待确定哪些患者最终将证明对化学疗法有抵抗力，因此需要新颖的治疗策略。阐明了扰动的表观基因组的分子后果，导致鉴定了一系列转导级联反应，这可能是针对治疗的。其中包括细胞周期蛋白D1/细胞周期蛋白依赖性激酶4和6，刺猬/Gli1，Wnt/ss-catenin，Zeste同源物2的增强子和Aurora激酶A等。目前正在临床前环境和AT/RT的实验性临床试验中评估，专门针对改变细胞表观遗传状态的这些途径或试剂的化合物。
Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ss-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT.