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

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-10-12 DOI:10.1093/neuonc/noae215
Matthew Gallitto, Xu Zhang, Genesis De Los Santos, Hong-Jian Wei, Ester Calvo Fernández, Shoufu Duan, Geoffrey Sedor, Nina Yoh, Danae Kokosi, J Carlos Angel, Yi-Fang Wang, Erin White, Connor J Kinslow, Xander Berg, Lorenzo Tomassoni, Fereshteh Zandkarimi, Iok In Christine Chio, Peter D Canoll, Jeffrey N Bruce, Neil A Feldstein, Robyn D Gartrell, Simon Cheng, James H Garvin, Stergios Zacharoulis, Robert J Wechsler-Reya, Jovana Pavisic, Andrea Califano, Zhiguo Zhang, Cheng-Chia Wu
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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靶向注射萘普卡西与放射治疗可改善弥漫中线胶质瘤的疗效。
背景:弥漫中线胶质瘤(DMG)是儿童中最具侵袭性的原发性脑肿瘤。以往所有关于全身用药作用的研究都未能证明其对生存有好处;唯一的治疗标准是放射治疗(RT)。在DMG中成功实施放射增敏策略仍是一个重要且前景广阔的研究方向。我们探索了Napabucasin(一种NAD(P)H醌脱氢酶1(NQO1)-可生物活化的活性氧(ROS)诱导剂)作为DMG潜在治疗性放射增敏剂的用途:在这项研究中,我们利用源自患者的 DMG 培养物进行了体外和体内试验,以阐明纳帕布卡辛的作用机制及其放射增敏特性。由于全身治疗通过血脑屏障(BBB)的渗透是DMG治疗成功的一个重要限制因素,我们探索了聚焦超声(FUS)和对流增强递送(CED)来克服BBB并最大限度地提高疗效:结果:萘普卡辛是一种强效的ROS诱导剂和DMG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 RT 联合治疗可改善局部控制。在正位小鼠模型中使用 CED 优化靶向给药后,我们证实了在 RT 治疗的同时使用 CED 给药纳帕布卡辛的新可行性和生存益处:由于几乎所有的 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 患者生存期的放射增敏疗法疗效的验证,为在这种毁灭性疾病中开展令人兴奋的放射增敏替代策略的新研究打开了大门,同时克服了 BBB 的局限性。
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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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