Publicaciones científicas
Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
Sriram Venneti # 1 , Abed Rahman Kawakibi # 1 , Sunjong Ji # 1 , Sebastian M Waszak # 2 3 4 , Stefan R Sweha # 1 5 , Mateus Mota # 1 , Matthew Pun # 1 , Akash Deogharkar 1 , Chan Chung 1 6 , Rohinton S Tarapore 7 , Samuel Ramage 7 , Andrew Chi 8 , Patrick Y Wen 9 , Isabel Arrillaga-Romany 10 , Tracy T Batchelor 11 , Nicholas A Butowski 2 , Ashley Sumrall 12 , Nicole Shonka 13 , Rebecca A Harrison 14 , John de Groot 2 , Minesh Mehta 15 , Matthew D Hall 15 , Doured Daghistani 15 , Timothy F Cloughesy 16 , Benjamin M Ellingson 16 , Kevin Beccaria 17 , Pascale Varlet 18 , Michelle M Kim 1 , Yoshie Umemura 1 , Hugh Garton 1 , Andrea Franson 1 , Jonathan Schwartz 13 , Rajan Jain 8 , Maureen Kachman 1 , Heidi Baum 1 , Charles F Burant 1 , Sophie L Mottl 3 , Rodrigo T Cartaxo 1 , Vishal John 1 , Dana Messinger 1 , Tingting Qin 1 , Erik Peterson 1 , Peter Sajjakulnukit 1 , Karthik Ravi 1 , Alyssa Waugh 1 , Dustin Walling 1 , Yujie Ding 1 , Ziyun Xia 1 , Anna Schwendeman 1 , Debra Hawes 19 , Fusheng Yang 19 , Alexander R Judkins 19 , Daniel Wahl 1 , Costas A Lyssiotis 1 , Daniel de la Nava 20 21 22 , Marta M Alonso 20 21 22 , Augustine Eze 23 , Jasper Spitzer 24 25 , Susanne V Schmidt 24 25 , Ryan J Duchatel 26 27 28 , Matthew D Dun 26 27 28 , Jason E Cain 29 30 , Li Jiang 31 32 , Sylwia A Stopka 33 34 , Gerard Baquer 33 , Michael S Regan 33 , Mariella G Filbin 31 32 , Nathalie Y R Agar 33 34 35 , Lili Zhao 1 , Chandan Kumar-Sinha 1 , Rajen Mody 1 , Arul Chinnaiyan 1 , Ryo Kurokawa 1 36 , Drew Pratt 37 , Viveka N Yadav 38 , Jacques Grill 39 , Cassie Kline 40 41 , Sabine Mueller 2 42 , Adam Resnick 40 41 , Javad Nazarian 43 44 45 , Joshua E Allen 7 , Yazmin Odia 15 , Sharon L Gardner 8 , Carl Koschmann 1
Abstract
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.
CITA DEL ARTÍCULO Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131
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