Ewing sarcoma is an aggressive pediatric tumor of the bone and soft tissue. The current standard of care is radiation and chemotherapy, and patients generally lack targeted therapies. One of the defining molecular features of this tumor type is the presence of significantly elevated levels of replication stress as compared to both normal cells and many other types of cancers, but the source of this stress is poorly understood. Tumors that harbor elevated levels of replication stress rely on the replication stress and DNA damage-response pathways to retain viability. Understanding the source of the replication stress in Ewing sarcoma may reveal novel therapeutic targets. Ewing sarcomagenesis is complex, and in this review, we discuss the current state of our knowledge regarding elevated replication stress and the DNA damage response in Ewing sarcoma, one contributor to the disease process. We will also describe how these pathways are being successfully targeted therapeutically in other tumor types, and discuss possible novel, evidence based therapeutic interventions in Ewing sarcoma. We hope that this consolidation will spark investigations that uncover new therapeutic targets and lead to the development of better treatment options for Ewing sarcoma patients. Implications: This review uncovers new therapeutic targets in Ewing Sarcoma and highlights replication stress as an exploitable vulnerability across multiple cancers.

中文翻译：

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利用复制压力作为一种新的治疗干预

尤文肉瘤是一种侵袭性儿童骨和软组织肿瘤。目前的护理标准是放疗和化疗，患者普遍缺乏靶向治疗。与正常细胞和许多其他类型的癌症相比，这种肿瘤类型的定义性分子特征之一是存在显着升高的复制压力水平，但人们对这种压力的来源知之甚少。具有高水平复制压力的肿瘤依赖于复制压力和 DNA 损伤反应途径来保持活力。了解尤文肉瘤中复制压力的来源可能会揭示新的治疗靶点。尤文肉瘤的发生很复杂，在这篇综述中，我们讨论了我们对尤文肉瘤中复制压力升高和 DNA 损伤反应的了解现状，尤文肉瘤是疾病过程的一个因素。我们还将描述这些途径如何成功地靶向治疗其他类型的肿瘤，并讨论在尤文肉瘤中可能的新的、基于证据的治疗干预措施。我们希望这种整合将激发发现新治疗靶点的研究，并为尤文肉瘤患者开发更好的治疗方案。启示：本综述揭示了尤文肉瘤的新治疗靶点，并强调复制压力是多种癌症中可利用的脆弱性。我们还将描述这些途径如何成功地靶向治疗其他类型的肿瘤，并讨论在尤文肉瘤中可能的新的、基于证据的治疗干预措施。我们希望这种整合将激发发现新治疗靶点的研究，并为尤文肉瘤患者开发更好的治疗方案。启示：本综述揭示了尤文肉瘤的新治疗靶点，并强调复制压力是多种癌症中可利用的脆弱性。我们还将描述这些途径如何成功地靶向治疗其他类型的肿瘤，并讨论在尤文肉瘤中可能的新的、基于证据的治疗干预措施。我们希望这种整合将激发发现新治疗靶点的研究，并为尤文肉瘤患者开发更好的治疗方案。启示：本综述揭示了尤文肉瘤的新治疗靶点，并强调复制压力是多种癌症中可利用的脆弱性。