PDF(Sci-hub)
Abstract：
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
摘要：
横纹肌肉瘤是最常见的小儿软组织肉瘤，是年轻患者癌症死亡的主要原因，需要新的治疗方案来改善预后。高风险患者包括患有转移性或复发性疾病和具有PAX3-FOXO1融合基因的肿瘤的患者,所述融合基因编码通过转录重编程驱动肿瘤发生的有效转录因子。Polo样激酶-1（PLK1）是一种丝氨酸/苏氨酸激酶，可磷酸化多种目标底物并改变其活性。PLK1充当有丝分裂的多效性主调节剂，并在应激后调节DNA复制。结合与许多癌症不良预后相关的高水平表达，包括横纹肌肉瘤,它是一个有吸引力的治疗目标。通过表征减少和抑制PLK1的分子和表型效应，包括PAX3-FOXO1融合蛋白的变化，在横纹肌肉瘤模型中得到了支持。然而,正如已经观察到的肿瘤再生长，需要采取组合策略。在这里，我们回顾了临床前证据，并考虑了PLK1抑制与促进细胞凋亡的药物组合的生物学原理。干扰PAX3-FOXO1的活性，并与微管去稳定药物如长春新碱协同作用。低剂量PLK1抑制剂volasertib联合长春新碱的临床前效果，广泛用于横纹肌肉瘤治疗，根据儿科环境中最近的临床数据，显示出特别的希望，这些数据支持可实现的volasertib剂量预测是有效的。包括PLK1抑制在内的新型治疗策略的进一步发展可能最终使患有横纹肌肉瘤和其他癌症的年轻患者受益。
