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
{"title":"Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.","authors":"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","doi":"10.1093/neuonc/noae215","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":null,"pages":null},"PeriodicalIF":16.4000,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/neuonc/noae215","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.