靶向递送使用放射疗法的纳帕巴素可以改善弥漫性中线神经胶质瘤的结局
Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma
影响因子:13.40000
分区:医学1区 Top / 临床神经病学1区 肿瘤学1区
发表日期:2025 Mar 07
作者:
Matthew Gallitto, Xu Zhang, Genesis De Los Santos, Hong-Jian Wei, Ester Calvo Fernández, Shoufu Duan, Geoffrey Sedor, Nina Yoh, Danae Kokossis, J Carlos Angel, Yi-Fang Wang, Erin White, Connor J Kinslow, Xander Berg, Lorenzo Tomassoni, Fereshteh Zandkarimi, Iok In Christine Chio, Peter Canoll, Jeffrey N Bruce, Neil A Feldstein, Robyn D Gartrell, Simon K Cheng, James H Garvin, Stergios Zacharoulis, Robert J Wechsler-Reya, Jovana Pavisic, Andrea Califano, Zhiguo Zhang, Cheng-Chia Wu
摘要
弥漫性中线神经胶质瘤（DMG）是儿童中最具侵略性的原发性脑肿瘤。所有检查系统性药物作用的研究都未能证明生存益处。唯一的护理标准是放射治疗（RT）。成功实施DMG中的放射敏化策略仍然是一项重要且有希望的调查途径。我们探索使用纳巴布糖蛋白，NAD（P）H喹酮脱氢酶1（NQO1） - 可生活性活性活性氧（ROS）诱导者作为DMG的潜在治疗性放射敏化剂。放射敏感性。由于通过血脑屏障（BBB）渗透全身治疗是DMG疗法成功的重要局限细胞毒性取决于NQO1。在皮下异种移植模型中，与RT的组合疗法可改善局部控制。在使用原位小鼠模型中使用CED优化靶向药物后，我们建立了与RT同时发生的Napabucasin CED的新颖的可行性和生存益处。几乎所有DMG患者都将接受RT，作为其治疗过程的一部分，我们对使用CED延长DMG Opens Intrantive radiation Dorions dore dore nor dor note dor note dore dor nor dore dor note dor note dor nortiation dore dor nor dor note dor note dor note dor note dor note dor note dor note dor的效率的验证在克服BBB的局限性时。版权所有。有关商业重复使用，请联系reprints@oup.com，以获取转载和翻译权以进行转载。所有其他权限都可以通过我们的restrimlink服务通过我们网站上文章页面上的“权限链接”获得 - 有关更多信息，请联系journals.permissions.permissions@oup.com。
Abstract
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.