靶向递送纳帕布昔单抗联合放疗改善弥漫性中线胶质瘤的治疗效果

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma

NEURO-ONCOLOGY

影响因子:13.4

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

DOI: 10.1093/neuonc/noae215

摘要

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。以往研究中关于系统用药作用的证据均未显示出生存优势，唯一的标准治疗仍为放射治疗（RT）。在DMG中成功应用放射增敏策略仍是一个关键且充满前景的研究方向。本研究探讨了纳帕布昔单抗（Napabucasin），一种NAD(P)H醌氧化还原酶1（NQO1）生物激活的活性氧（ROS）诱导剂，作为潜在的放射增敏剂的作用机制及其在DMG中的应用。在体外和体内模型中，我们使用患者源性DMG细胞进行试验，阐明Napabucasin的作用机制及其放射增敏特性。由于系统治疗穿越血脑屏障（BBB）存在较大限制，我们探索了聚焦超声（FUS）和对流增强递送（CED）技术，以突破BBB，最大化治疗效果。结果显示，Napabucasin在DMG中是一种强效的ROS诱导剂和放射增敏剂，其诱导ROS的能力和细胞毒性依赖于NQO1。在皮下异种模型中，联合放疗的治疗显著改善局部控制。经过优化在正位小鼠模型中应用的目标药物递送（CED），我们首次建立了结合放疗的Napabucasin通过CED的可行性及生存益处。由于几乎所有DMG患者在治疗过程中都会接受放疗，我们验证了利用CED延长DMG患者生存的放射增敏疗法的有效性，为未来开发新的放射增敏策略提供了可能，同时克服了BBB的限制。© 作者（们）2024年。由牛津大学出版社代表神经肿瘤学会出版。所有权利保留。如需商业用途，请联系reprints@oup.com获取重印和翻译授权。本文页面上的Permissions链接还可通过RightsLink服务获取其他权限。如需更多信息，请联系journals.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.