弥漫性中线胶质瘤（DMG）是儿童中最具侵袭性的原发性脑肿瘤。之前所有研究全身性药物作用的研究都未能证明其对生存有益处。唯一的护理标准是放射治疗 (RT)。在 DMG 中成功实施放射增敏策略仍然是一个重要且有前途的研究途径。我们探索使用 Napabucasin（一种 NAD(P)H 醌脱氢酶 1 (NQO1)-生物可激活的活性氧 (ROS)-诱导剂）作为 DMG 中潜在的治疗性放射增敏剂。在这项研究中，我们进行了体外和体内测定使用患者来源的 DMG 培养物来阐明 Napabucasin 的作用机制及其放射增敏特性。由于全身治疗穿过血脑屏障 (BBB) 是 DMG 治疗成功的一个重大限制，因此我们探索聚焦超声 (FUS) 和对流增强递送 (CED) 来克服 BBB 并最大限度地提高治疗效果。 Napabucasin是 DMG 中有效的 ROS 诱导剂和放射增敏剂，治疗介导的 ROS 产生和细胞毒性依赖于 NQO1。在皮下异种移植模型中，与放疗的联合治疗可改善局部控制。在原位小鼠模型中使用 CED 优化靶向药物递送后，我们建立了 Napabucasin CED 与 RT 同时进行的新的可行性和生存益处。由于几乎所有 DMG 患者都会接受 RT 作为其治疗过程的一部分，因此我们验证了 Napabucasin 的疗效使用 CED 的放射增敏疗法延长 DMG 的生存期，为这种毁灭性疾病中替代放射增敏策略的令人兴奋的新颖研究打开了大门，同时克服了 BBB 的局限性。© 作者 2024 年。由牛津大学出版社代表医学会出版神经肿瘤学。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG.In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy.Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT.As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.