Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma

摘要 儿童肌肉癌泡状横纹肌肉瘤(ARMS)在转移时一般不能存活。 然而，ARMS通常最初在临床上对化疗有反应。关于……的原因 复发，临床医生观察到，PAX3：Foxo1癌基因存在于大多数ARM病例中 治疗耐药，导致10年存活率下降45%。在解释中，我们报告了PAX3：Foxo1 促进G2/M检查点适应(对DNA断裂和有丝分裂灾难的耐受性)。因此，驾驶诊所 挑战是通过对抗PAX3：Foxo1来克服复发。我们发表了PAX3：Foxo1可以 新组蛋白去乙酰化酶抑制剂Eninostat在药理上的沉默。我们戏剧性地发现了内抑素 提高手臂对一线化疗的敏感性。从机制上讲，我们最近发表的研究表明 HDAC3-SMARCA4-MIR-27A-PAX3：Foxo1调节电路在ARM中。与此同时，我们发现了 SMARCA4的表达在融合阳性的手臂中独特地升高，并且手臂选择性的SMARCA4 表达是肿瘤细胞生存的关键的长期易感性。这些结果表明SMARCA4有一个 融合阳性武器控制PAX3的关键作用：Foxo1与短期和长期化疗敏感性 肿瘤细胞长期维持。我们假设PAX3：Foxo1+手臂可以制造出更多 复发时化疗敏感，通过表观遗传沉默PAX3：Foxo1复发的可能性较小。因此，我们的目标是 目的：(1)通过SWI/SNF BAF复合体描述SMARCA4作为癌基因在ARM中的非典型作用， 和(2)直接PAX3：Foxo1抑制与上游SMARCA4/A2抑制与 当与复发化疗药物和非化疗药物联合使用时。从这些 结果，我们希望了解横纹肌肉瘤的分子基础。

SUMMARY The childhood muscle cancer alveolar rhabdomyosarcoma (ARMS) is generally not survivable when metastatic. However, ARMS does usually respond clinically to chemotherapy initially. With respect to the cause of recurrences, clinicians observe that the PAX3:FOXO1 oncogene present in most ARMS cases mediates treatment resistance, causing a 45% drop in 10-year survival. In explanation, we reported that PAX3:FOXO1 facilitates G2/M checkpoint adaptation (tolerance of DNA breaks & mitotic catastrophe). Thus, the driving clinical challenge is to overcome recurrence by counteracting PAX3:FOXO1. We published that PAX3:FOXO1 can be pharmacologically silenced by entinostat, a novel histone deacetylase inhibitor. We find entinostat dramatically improves ARMS sensitivity to frontline chemotherapy. Mechanistically, our recently published studies implicate an HDAC3 – SMARCA4 – miR-27a – PAX3:FOXO1 regulatory circuitry in ARMS. In parallel we have uncovered that SMARCA4 expression is uniquely elevated in fusion positive ARMS, and that ARMS-selective SMARCA4 expression is a pivotal long-term susceptibility in tumor cell survival. These results point to SMARCA4 having a key role in fusion positive ARMS – controlling PAX3:FOXO1 and chemotherapy sensitivity in the short-term and tumor cell maintenance long-term. We hypothesize that PAX3:FOXO1+ ARMS can be made more chemosensitive at relapse and less likely to recur by epigenetically silencing PAX3:FOXO1. Thus, our aims are to: (1) Delineate the atypical role of SMARCA4 as an oncogene in ARMS via the SWI/SNF BAF complex, and (2) Test efficacy of direct PAX3:FOXO1 inhibition versus upstream SMARCA4/A2 inhibition versus entinostat when combined with relapse chemotherapy and non-chemotherapy agents. From these results, we hope to understand rhabdomyosarcoma molecular underpinnings.