横纹肌肉瘤（RMS）是最常见的儿童软组织肉瘤。对于肺泡亚型 (ARMS)，PAX3::FOXO1 融合基因和/或转移的存在是不良结果的有力预测因素。转移性 PAX3::FOXO1 ARMS 通常最初对化疗有反应，但随后会复发并产生耐药性，大多数患者在诊断后无法存活超过 8 年。过去 10 年来，尚无针对患者的治疗性 II 期或 III 期临床试验 (ARST0921)。因此，转移性 ARMS 代表了显着未满足的临床需求。 ARMS 中的化疗耐药性先前被归因于 PAX3::FOXO1 介导的细胞周期检查点适应，该适应是由 HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 电路介导的，该电路可通过 HDAC3 抑制来破坏。在这项研究中，我们研究了表观遗传调节剂恩替司他（一种 I 类组蛋白脱乙酰酶 (HDAC1-3) 抑制剂）与 RMS 特异性化疗相结合在 RMS 患者来源的异种移植 (PDX) 模型中的治疗效果。我们在三种 PAX3::FOXO1 ARMS 小鼠模型中确定了复发特异性化疗与恩替司他临床相关药物暴露之间的单药、累加或协同关系。该临床前数据为恩替司他的临床研究提供了进一步的理论依据，恩替司他在儿科 I 期临床试验 (ADVL1513) 中已知具有良好的耐受性。© 2024。作者。

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).© 2024. The Author(s).