- Title
- Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways
- Creator
- Venneti, Sriram; Kawakibi, Abed Rahman; 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; Ji, Sunjong; Mehta, M; Hall, MD; Daghistani, D; Cloughesy, TF; Ellingson, BM; Beccaria, K; Varlet, P; Kim, MM; Umemura, Y; Garton, H; Waszak, Sebastian M.; Franson, A; Schwartz, J; Jain, R; Kachman, M; Baum, H; Burant, CF; Mottl, SL; Cartaxo, RT; John, V; Messinger, D; Sweha, StefanR; Qin, T; Peterson, E; Sajjakulnukit, P; Ravi, K; Waugh, A; Walling, D; Ding, Y; Xia, Z; Schwendeman, A; Hawes, D; Mota, Mateus; Yang, F; Judkins, AR; Wahl, D; Lyssiotis, CA; de la Nava, D; Alonso, MM; Eze, A; Spitzer, J; Schmidt, SV; Duchatel, Ryan J.; Pun, Matthew; Dun, Matthew D.; Cain, JE; Jiang, L; Stopka, SA; Baquer, G; Regan, MS; Filbin, MG; Agar, NYR; Zhao, L; Kumar-Sinha, C; Deogharkar, Akash; Mody, R; Chinnaiyan, A; Kurokawa, R; Pratt, D; Yadav, VN; Grill, J; Kline, C; Mueller, S; Resnick, A; Nazarian, J; Chung, Chan; Allen, JE; Odia, Y; Gardner, SL; Koschmann, C; Tarapore, Rohinton S.
- Relation
- Cancer Discovery Vol. 13, Issue 11, p. 2370-2393
- Publisher Link
- http://dx.doi.org/10.1158/2159-8290.CD-23-0131
- Publisher
- American Association for Cancer Research
- Resource Type
- journal article
- Date
- 2023
- Description
- 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 multisite 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.
- Subject
- diffuse midline glioma (DMG); clinical outcomes; tumor sequencing; tissue/cerebrospinal fluid; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1494889
- Identifier
- uon:53913
- Identifier
- ISSN:2159-8274
- Rights
- x
- Language
- eng
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