Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Sriram Venneti; Abed Rahman Kawakibi; Sunjong Ji; Sebastian M. Waszak; Stefan R. Sweha; Mateus Mota; Matthew Pun; Akash Deogharkar; Chan Chung; Rohinton S. Tarapore; Samuel Ramage; Andrew Chi; Patrick Y. Wen; Isabel Arrillaga-Romany; Tracy T. Batchelor; Nicholas A. Butowski; Ashley Sumrall; Nicole Shonka; Rebecca A. Harrison; John de Groot; Minesh Mehta; Matthew D. Hall; Doured Daghistani; Timothy F. Cloughesy; Benjamin M. Ellingson; Kevin Beccaria; Pascale Varlet; Michelle M. Kim; Yoshie Umemura; Hugh Garton; Andrea Franson; Jonathan Schwartz; Rajan Jain; Maureen Kachman; Heidi Baum; Charles F. Burant; Sophie L. Mottl; Rodrigo T. Cartaxo; Vishal John; Dana Messinger; Tingting Qin; Erik Peterson; Peter Sajjakulnukit; Karthik Ravi; Alyssa Waugh; Dustin Walling; Yujie Ding; Ziyun Xia; Anna Schwendeman; Debra Hawes; Fusheng Yang; Alexander R. Judkins; Daniel Wahl; Costas A. Lyssiotis; Daniel de la Nava; Marta M. Alonso; Augustine Eze; Jasper Spitzer; Susanne V. Schmidt; Ryan J. Duchatel; Matthew D. Dun; Jason E. Cain; Li Jiang; Sylwia A. Stopka; Gerard Baquer; Michael S. Regan; Mariella G. Filbin; Nathalie Y.R. Agar; Lili Zhao; Chandan Kumar-Sinha; Rajen Mody; Arul Chinnaiyan; Ryo Kurokawa; Drew Pratt; Viveka N. Yadav; Jacques Grill; Cassie Kline; Sabine Mueller; Adam Resnick; Javad Nazarian; Joshua E. Allen; Yazmin Odia; Sharon L. Gardner; Carl Koschmann

doi:10.1158/2159-8290.CD-23-0131

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Sriram Venneti
, Abed Rahman Kawakibi
, Sunjong Ji
, Sebastian M. Waszak
, Stefan R. Sweha
, Mateus Mota
, Matthew Pun
, Akash Deogharkar
, Chan Chung
, Rohinton S. Tarapore
, Samuel Ramage
, Andrew Chi
, Patrick Y. Wen
, Isabel Arrillaga-Romany
, Tracy T. Batchelor
, Nicholas A. Butowski
, Ashley Sumrall
, Nicole Shonka
, Rebecca A. Harrison
, John de Groot

Minesh Mehta, Matthew D. Hall, Doured Daghistani, Timothy F. Cloughesy, Benjamin M. Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M. Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F. Burant, Sophie L. Mottl, Rodrigo T. Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R. Judkins, Daniel Wahl, Costas A. Lyssiotis, Daniel de la Nava, Marta M. Alonso, Augustine Eze, Jasper Spitzer, Susanne V. Schmidt, Ryan J. Duchatel, Matthew D. Dun, Jason E. Cain, Li Jiang, Sylwia A. Stopka, Gerard Baquer, Michael S. Regan, Mariella G. Filbin, Nathalie Y.R. Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N. Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E. Allen, Yazmin Odia, Sharon L. Gardner, Carl Koschmann

Department of New Biology

University of Michigan, Ann Arbor
University of California at San Francisco
University of Oslo
Swiss Federal Institute of Technology Lausanne
Memorial Sloan-Kettering Cancer Center
Chimerix, Inc.
New York University
Dana-Farber Cancer Institute
Massachusetts General Hospital
Brigham and Women’s Hospital
Levine Cancer Institute
Mayo Clinic Rochester, MN
University of British Columbia
Miami Cancer Institute
University of California at Los Angeles
Université Paris Cité
Centre Hospitalier Sainte-Anne
University of Southern California
Navarra Medical Research Institute
University of Navarra
Children’s National Hospital
University of Bonn
University of Newcastle
Hunter Medical Research Institute, Australia
Mark Hughes Foundation Centre for Brain Cancer Research
Hudson Institute of Medical Research
Monash University
Harvard University
The University of Tokyo
National Institutes of Health
Department of Pediatrics at Children’s Mercy Research Institute
Gustave Roussy and University Paris-Saclay
The Children's Hospital of Philadelphia
University of Pennsylvania
University of Zurich
Children's National Medical Center
George Washington University

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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 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.

Original language	English
Pages (from-to)	2370-2393
Number of pages	24
Journal	Cancer Discovery
Volume	13
Issue number	11
DOIs	https://doi.org/10.1158/2159-8290.CD-23-0131
State	Published - 1 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.

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10.1158/2159-8290.CD-23-0131

Cite this

Venneti, S., Kawakibi, A. R., Ji, S., Waszak, S. M., Sweha, S. R., Mota, M., Pun, M., Deogharkar, A., Chung, C., Tarapore, R. S., Ramage, S., Chi, A., Wen, P. Y., Arrillaga-Romany, I., Batchelor, T. T., Butowski, N. A., Sumrall, A., Shonka, N., Harrison, R. A., ... Koschmann, C. (2023). Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Cancer Discovery, 13(11), 2370-2393. https://doi.org/10.1158/2159-8290.CD-23-0131

@article{219f7d3b7af74fd094def71b0a002c4a,

title = "Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways",

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 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.",

author = "Sriram Venneti and Kawakibi, \{Abed Rahman\} and Sunjong Ji and Waszak, \{Sebastian M.\} and Sweha, \{Stefan R.\} and Mateus Mota and Matthew Pun and Akash Deogharkar and Chan Chung and Tarapore, \{Rohinton S.\} and Samuel Ramage and Andrew Chi and Wen, \{Patrick Y.\} and Isabel Arrillaga-Romany and Batchelor, \{Tracy T.\} and Butowski, \{Nicholas A.\} and Ashley Sumrall and Nicole Shonka and Harrison, \{Rebecca A.\} and \{de Groot\}, John and Minesh Mehta and Hall, \{Matthew D.\} and Doured Daghistani and Cloughesy, \{Timothy F.\} and Ellingson, \{Benjamin M.\} and Kevin Beccaria and Pascale Varlet and Kim, \{Michelle M.\} and Yoshie Umemura and Hugh Garton and Andrea Franson and Jonathan Schwartz and Rajan Jain and Maureen Kachman and Heidi Baum and Burant, \{Charles F.\} and Mottl, \{Sophie L.\} and Cartaxo, \{Rodrigo T.\} and Vishal John and Dana Messinger and Tingting Qin and Erik Peterson and Peter Sajjakulnukit and Karthik Ravi and Alyssa Waugh and Dustin Walling and Yujie Ding and Ziyun Xia and Anna Schwendeman and Debra Hawes and Fusheng Yang and Judkins, \{Alexander R.\} and Daniel Wahl and Lyssiotis, \{Costas A.\} and \{de la Nava\}, Daniel and Alonso, \{Marta M.\} and Augustine Eze and Jasper Spitzer and Schmidt, \{Susanne V.\} and Duchatel, \{Ryan J.\} and Dun, \{Matthew D.\} and Cain, \{Jason E.\} and Li Jiang and Stopka, \{Sylwia A.\} and Gerard Baquer and Regan, \{Michael S.\} and Filbin, \{Mariella G.\} and Agar, \{Nathalie Y.R.\} and Lili Zhao and Chandan Kumar-Sinha and Rajen Mody and Arul Chinnaiyan and Ryo Kurokawa and Drew Pratt and Yadav, \{Viveka N.\} and Jacques Grill and Cassie Kline and Sabine Mueller and Adam Resnick and Javad Nazarian and Allen, \{Joshua E.\} and Yazmin Odia and Gardner, \{Sharon L.\} and Carl Koschmann",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = nov,

day = "1",

doi = "10.1158/2159-8290.CD-23-0131",

language = "English",

volume = "13",

pages = "2370--2393",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Venneti, S, Kawakibi, AR, Ji, S, Waszak, SM, Sweha, SR, Mota, M, Pun, M, Deogharkar, A, Chung, C, Tarapore, RS, Ramage, S, Chi, A, Wen, PY, Arrillaga-Romany, I, Batchelor, TT, Butowski, NA, Sumrall, A, Shonka, N, Harrison, RA, de Groot, J, Mehta, M, Hall, MD, Daghistani, D, Cloughesy, TF, Ellingson, BM, Beccaria, K, Varlet, P, Kim, MM, Umemura, Y, Garton, H, Franson, A, Schwartz, J, Jain, R, Kachman, M, Baum, H, Burant, CF, Mottl, SL, Cartaxo, RT, John, V, Messinger, D, Qin, T, Peterson, E, Sajjakulnukit, P, Ravi, K, Waugh, A, Walling, D, Ding, Y, Xia, Z, Schwendeman, A, Hawes, D, Yang, F, Judkins, AR, Wahl, D, Lyssiotis, CA, de la Nava, D, Alonso, MM, Eze, A, Spitzer, J, Schmidt, SV, Duchatel, RJ, Dun, MD, Cain, JE, Jiang, L, Stopka, SA, Baquer, G, Regan, MS, Filbin, MG, Agar, NYR, Zhao, L, Kumar-Sinha, C, Mody, R, Chinnaiyan, A, Kurokawa, R, Pratt, D, Yadav, VN, Grill, J, Kline, C, Mueller, S, Resnick, A, Nazarian, J, Allen, JE, Odia, Y, Gardner, SL & Koschmann, C 2023, 'Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways', Cancer Discovery, vol. 13, no. 11, pp. 2370-2393. https://doi.org/10.1158/2159-8290.CD-23-0131

TY - JOUR

T1 - Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

AU - Venneti, Sriram

AU - Kawakibi, Abed Rahman

AU - Ji, Sunjong

AU - Waszak, Sebastian M.

AU - Sweha, Stefan R.

AU - Mota, Mateus

AU - Pun, Matthew

AU - Deogharkar, Akash

AU - Chung, Chan

AU - Tarapore, Rohinton S.

AU - Ramage, Samuel

AU - Chi, Andrew

AU - Wen, Patrick Y.

AU - Arrillaga-Romany, Isabel

AU - Batchelor, Tracy T.

AU - Butowski, Nicholas A.

AU - Sumrall, Ashley

AU - Shonka, Nicole

AU - Harrison, Rebecca A.

AU - de Groot, John

AU - Mehta, Minesh

AU - Hall, Matthew D.

AU - Daghistani, Doured

AU - Cloughesy, Timothy F.

AU - Ellingson, Benjamin M.

AU - Beccaria, Kevin

AU - Varlet, Pascale

AU - Kim, Michelle M.

AU - Umemura, Yoshie

AU - Garton, Hugh

AU - Franson, Andrea

AU - Schwartz, Jonathan

AU - Jain, Rajan

AU - Kachman, Maureen

AU - Baum, Heidi

AU - Burant, Charles F.

AU - Mottl, Sophie L.

AU - Cartaxo, Rodrigo T.

AU - John, Vishal

AU - Messinger, Dana

AU - Qin, Tingting

AU - Peterson, Erik

AU - Sajjakulnukit, Peter

AU - Ravi, Karthik

AU - Waugh, Alyssa

AU - Walling, Dustin

AU - Ding, Yujie

AU - Xia, Ziyun

AU - Schwendeman, Anna

AU - Hawes, Debra

AU - Yang, Fusheng

AU - Judkins, Alexander R.

AU - Wahl, Daniel

AU - Lyssiotis, Costas A.

AU - de la Nava, Daniel

AU - Alonso, Marta M.

AU - Eze, Augustine

AU - Spitzer, Jasper

AU - Schmidt, Susanne V.

AU - Duchatel, Ryan J.

AU - Dun, Matthew D.

AU - Cain, Jason E.

AU - Jiang, Li

AU - Stopka, Sylwia A.

AU - Baquer, Gerard

AU - Regan, Michael S.

AU - Filbin, Mariella G.

AU - Agar, Nathalie Y.R.

AU - Zhao, Lili

AU - Kumar-Sinha, Chandan

AU - Mody, Rajen

AU - Chinnaiyan, Arul

AU - Kurokawa, Ryo

AU - Pratt, Drew

AU - Yadav, Viveka N.

AU - Grill, Jacques

AU - Kline, Cassie

AU - Mueller, Sabine

AU - Resnick, Adam

AU - Nazarian, Javad

AU - Allen, Joshua E.

AU - Odia, Yazmin

AU - Gardner, Sharon L.

AU - Koschmann, Carl

PY - 2023/11/1

Y1 - 2023/11/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85173862801

U2 - 10.1158/2159-8290.CD-23-0131

DO - 10.1158/2159-8290.CD-23-0131

M3 - Article

C2 - 37584601

AN - SCOPUS:85173862801

SN - 2159-8274

VL - 13

SP - 2370

EP - 2393

JO - Cancer Discovery

JF - Cancer Discovery

IS - 11

ER -

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

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