Abstract: ATRT is a highly aggressive and rare pediatric CNS tumor of very young children. Its genetic hallmark is bi-allelic inactivation of SMARCB1 encoding INI1. Rarely SMARCA4 encoding BRG1 is affected. Up to 30% are associated with constitutional heterozygous pathogenic variants in one of the two genes, giving rise to the Rhabdoid-Tumor-Predisposition-Syndromes (RTPS) 1 and 2. Characteristic DNA methylation profiles distinguish ATRT from other SMARCB1-deficient entities. Three distinct subtypes ATRT-MYC, -TYR, and -SHH are on record. ATRT-SHH may be further divided into the subgroups ATRT-SHH1A, -SHH1B, and -SHH2. The cure of ATRT remains challenging, notwithstanding an increasing understanding of molecular pathomechanisms and genetic background. The implementation of multimodal institutional treatment protocols has improved prognosis. Regardless of treatment approaches, clinical risk factors such as age, metastases, and DNA methylation subtype affect survival probability. We provide a critical appraisal of current conventional multimodal regimens and emerging targeted treatment approaches investigated in clinical trials and entity-specific registries. Intense treatment approaches featuring radiotherapy (RT) and high-dose chemotherapy (HDCT) face the difficulty of balancing tumor control and treatment-related toxicity. Current approaches focus on minimizing radiation fields by proton beam therapy or to withhold RT in HDCT-only approaches. Still, a 40– 75% relapse rate upon first-line treatment reveals the need for novel treatment strategies in primary and even more in recurrent/refractory (r/r) disease. Among targeted treatments, immune checkpoint inhibitors and epigenetically active agents appear most promising. Success remains limited in single agent approaches. We hypothesize that mechanism-informed combination therapy will enhance response, as the low mutational burden of ATRT may contribute to acquiring resistance to single targeted agents. As DNA methylation group-specific gene expression profiles appear to influence response to distinct agents, the future treatment of ATRT should respect clinical and biological heterogeneity in risk group adjusted treatment protocols.

Keywords: SWI/SNF related matrix associated, actin dependent regulator of chromatin, subfamily b, member 1, SMARCB1, atypical teratoid rhabdoid tumor, ATRT, central nervous system, CNS, treatment, pediatric, cell cycle


中文翻译：

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ATRT 当前的分子和临床前景——与未来疗法的联系

摘要： ATRT 是一种高度侵袭性且罕见的儿童中枢神经系统肿瘤。其遗传标志是编码 INI1 的SMARCB1双等位基因失活。编码 BRG1 的SMARCA4很少受到影响。高达 30% 与两个基因之一的组成性杂合致病性变异相关，从而产生横纹肌样肿瘤易感综合征 (RTPS) 1 和 2。特征性 DNA 甲基化谱将 ATRT 与其他SMARCB1缺陷实体区分开来。三种不同的亚型 ATRT-MYC、-TYR 和 -SHH 已记录在案。ATRT-SHH可以进一步分为子组ATRT-SHH1A、-SHH1B和-SHH2。尽管人们对分子病理机制和遗传背景的了解不断增加，但 ATRT 的治愈仍然具有挑战性。多模式机构治疗方案的实施改善了预后。无论采用何种治疗方法，年龄、转移和 DNA 甲基化亚型等临床危险因素都会影响生存概率。我们对临床试验和特定实体注册中研究的当前传统多模式治疗方案和新兴靶向治疗方法进行严格评估。以放疗（RT）和高剂量化疗（HDCT）为特色的强化治疗方法面临着平衡肿瘤控制和治疗相关毒性的困难。目前的方法侧重于通过质子束治疗最小化辐射场或在仅 HDCT 方法中保留 RT。尽管如此，一线治疗后 40-75% 的复发率表明，原发性疾病需要新的治疗策略，而复发/难治性 (r/r) 疾病则更需要新的治疗策略。在靶向治疗中，免疫检查点抑制剂和表观遗传活性药物似乎最有前途。单一代理方法的成功仍然有限。我们假设基于机制的联合治疗将增强疗效，因为 ATRT 的低突变负荷可能有助于获得对单一靶向药物的耐药性。由于 DNA 甲基化组特异性基因表达谱似乎会影响对不同药物的反应，因此 ATRT 的未来治疗应尊重风险组调整治疗方案中的临床和生物学异质性。

关键词： SWI/SNF 相关基质相关、肌动蛋白依赖性染色质调节因子、b 亚家族、成员 1、SMARCB1、非典型畸胎瘤样横纹肌瘤、ATRT、中枢神经系统、CNS、治疗、儿科、细胞周期