دورية أكاديمية
Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
| العنوان: | Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways |
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| المؤلفون: | Venneti, Sriram, Kawakibi, Abed Rahman, Ji, Sunjong, Waszak, Sebastian M., Sweha, Stefan R., Mota, Mateus, Pun, Matthew, Deogharkar, Akash, Chung, Chan, Tarapore, Rohinton S., Ramage, Samuel, Chi, Andrew, Wen, Patrick Y., Arrillaga-Romany, Isabel, Batchelor, Tracy T., Butowski, Nicholas A., Sumrall, Ashley, Shonka, Nicole, Harrison, Rebecca A., de Groot, John, Mehta, Minesh, Hall, Matthew D., Daghistani, Doured, Cloughesy, Timothy F., Ellingson, Benjamin M., Beccaria, Kevin, Varlet, Pascale, Kim, Michelle M., Umemura, Yoshie, Garton, Hugh, Franson, Andrea, Schwartz, Jonathan, Jain, Rajan, Kachman, Maureen, Baum, Heidi, Burant, Charles F., Mottl, Sophie L., Cartaxo, Rodrigo T., John, Vishal, Messinger, Dana, Qin, Tingting, Peterson, Erik, Sajjakulnukit, Peter, Ravi, Karthik, Waugh, Alyssa, Walling, Dustin, Ding, Yujie, Xia, Ziyun, Schwendeman, Anna, Hawes, Debra, Yang, Fusheng, Judkins, Alexander R., Wahl, Daniel, Lyssiotis, Costas A., de la Nava, Daniel, Alonso, Marta M., Eze, Augustine, Spitzer, Jasper, Schmidt, Susanne V., Duchatel, Ryan J., Dun, Matthew D., Cain, Jason E., Jiang, Li, Stopka, Sylwia A., Baquer, Gerard, Regan, Michael S., Filbin, Mariella G., Agar, Nathalie Y. R., Zhao, Lili, Kumar-Sinha, Chandan, Mody, Rajen, Chinnaiyan, Arul, Kurokawa, Ryo, Pratt, Drew, Yadav, Viveka N., Grill, Jacques, Kline, Cassie, Mueller, Sabine, Resnick, Adam, Nazarian, Javad, Allen, Joshua E., Odia, Yazmin, Gardner, Sharon L., Koschmann, Carl |
| بيانات النشر: | American Association for Cancer Research |
| سنة النشر: | 2024 |
| المجموعة: | DGIST Scholar (Daegu Gyeongbuk Institute of Science & Technology) |
| مصطلحات موضوعية: | L-2-HYDROXYGLUTARATE, ONCOMETABOLITE, PROGRESSION, EXPRESSION, H3K27ME3, PROTEINS, PEDIATRIC HIGH-GRADE, METHYLATION, SURVIVAL, MUTATION |
| الوصف: | Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. © 2023 The Authors; Published by the American Association for Cancer Research. ; TRUE |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2159-8274 |
| العلاقة: | http://hdl.handle.net/20.500.11750/47761Test; 2-s2.0-85173862801; Cancer Discovery, v.13, no.11, pp.2370 - 2393 |
| DOI: | 10.1158/2159-8290.cd-23-0131 |
| الإتاحة: | https://doi.org/20.500.11750/47761Test https://doi.org/10.1158/2159-8290.cd-23-0131Test https://hdl.handle.net/20.500.11750/47761Test |
| رقم الانضمام: | edsbas.B4DD032A |
| قاعدة البيانات: | BASE |
| تدمد: | 21598274 |
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| DOI: | 10.1158/2159-8290.cd-23-0131 |