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 GrootMinesh 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

Hudson Institute - Department of Molecular and Translational Science

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

35 Citations (Scopus)

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
Publication status	Published - Nov 2023

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10.1158/2159-8290.CD-23-0131Licence: CC BY-NC-ND

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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{3a0e126625744cd49c217480e1d851bd,

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 = "Funding Information: S.M. Waszak reports grants from The Research Council of Norway, the University of Oslo, and The South-Eastern Norway Regional Health Authority during the conduct of the study. R.S. Tarapore reports other support from Chimerix during the conduct of the study; other support from Chimerix outside the submitted work; and is an employee and stockholder of Chimerix S. Ramage reports personal fees from Chimerix during the conduct of the study, as well as other support from Chimerix outside the submitted work. A. Chi reports other support from Bright Peak Therapeutics and Mirati Therapeutics outside the submitted work, as well as a patent for methods for treatment of lung cancers pending. P.Y. Wen reports personal fees and other support from Chimerix during the conduct of the study. I. Arrillaga-Romany reports personal fees from Boehringer Ingelheim, and grants from Astex Pharmaceuticals and GSK outside the submitted work. T.T. Batchelor reports grants from ONO and the NIH, and personal fees from UpToDate outside the submitted work. A. Sumrall reports grants from Chimerix during the conduct of the study. R.A. Harrison reports other support from Pfizer and EMD Serono outside the submitted work. J. de Groot reports personal fees from Chimerix during the conduct of the study. M. Mehta reports other support from Oncoceutics and Chimerix during the conduct of the study, as well as personal fees from Kazia, Novocure, Zap, Xoft, Karyopharm, and Sapience outside the submitted work. M.D. Hall is a Voting Member, Proton Collaborative Group Executive Council (unpaid); treasurer, Proton Therapy Cooperative Group of North America (unpaid); cochair, Pediatric Subcommittee, Proton Therapy Cooperative Group (unpaid); and Radiation Oncology Study Committee Member, Children{\textquoteright}s Oncology Group ACCL2031, ACNS2021, and ACNS2321 studies (unpaid). T.F. Cloughesy reports personal fees from Chimerix during the conduct of the study; personal fees from Katmai Pharmaceuticals, Erasca, Servier, Global Coalition for Adaptive Research, Roche, Sapience, Venrock, Blue Rock, Vida, Lista Therapeutics, Novartis, Kiyetic, Stemline, Break Through Cancer, Kintara, Ideology Health, COO, Sonalasence, Sagimet, Reovirus, Agios, Boehringer Ingelheim, VBL, Novocure, and Jubilant outside the submitted work; patent 11,377,451 issued, licensed, and with royalties paid from Katmai; and that The Regents of the University of California (T.F. Cloughesy employer) has licensed intellectual property coinvented by T.F. Cloughesy to Katmai Pharmaceuticals. B.M. Ellingson reports personal fees from MedQIA during the conduct of the study, as well as personal fees from Medicenna, Servier, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Monteris, Alpheus Medical, Curtana Pharma, Sagimet Biosciences, Sapience Therapeutics, Carthera, Imaging Endpoints, and Orbus Therapeutics, and grants and personal fees from Siemens and Neosoma outside the submitted work. Y. Umemura reports grants from Chimerix during the conduct of the study, as well as grants from Chimerix, Servier, ONO Pharmaceutical, and Gateway for Cancer Research, and personal fees from Tempus outside the submitted work. A. Franson reports other support from Day One Biotherapeutics outside the submitted work. N. Agar reports nonfinancial support from Bruker and Thermo Fisher, and other support from EMD Serono outside the submitted work. J. Grill reports nonfinancial support from Chimerix during the conduct of the study. C. Kline reports nonfinancial support and other support from Oncoceutics/Chimerix during the conduct of the study, as well as nonfinancial support and other support from Bristol Myers Squibb, Curis, Midatech, Kazia, Day One Biopharmaceuticals, and Regeneron outside the submitted work. J.E. Allen reports other support from Chimerix during the conduct of the study, as well as a patent for ONC201 and imipridones pending, issued, licensed, and with royalties paid from Chimerix. Y. Odia reports grants from Chi-merix during the conduct of the study. S.L. Gardner reports grants from the Making Headway Foundation during the conduct of the study. No disclosures were reported by the other authors. Funding Information: The authors thank the patients and their families for participating in this study. This study was financially supported by NIH grant R01-NS119231 (C. Koschmann), NIH grant R01-NS124607 (C. Koschmann), NIH grant R01-NS110572 (S. Venneti), NIH grant R01-CA261926 (S. Venneti), DOD grant CA201129P1 (C. Koschmann), University of Michigan Chad Carr Pediatric Brain Tumor Center (C. Koschmann and S. Venneti), The Evans Family (C. Koschmann), ChadTough Defeat DIPG Foundation (C. Koschmann, S. Venneti, M. Mota, and C. Chung), the Al Musella Foundation (C. Koschmann), Catching Up with Jack (C. Koschmann), Pediatric Brain Tumor Foundation (C. Koschmann), Prayers from Maria Foundation (C. Koschmann), Michael Miller Memorial Foundation (C. Koschmann), Morgan Behen Golf Classic (C. Koschmann), Yuvaan Tiwari Foundation (C. Koschmann), Sontag Foundation (S. Venneti), Alex{\textquoteright}s Lemonade Stand Foundation (S. Venneti), Hyundai Hope Foundation (S. Venneti), NIH Clinical Sequencing Exploratory Research Award Grant 1UM1HG006508 for PEDS-MIONCOSEQ Study (A. Chinnaiyan), Research Council of Norway 187615 (S.M. Waszak), The South-Eastern Norway Regional Health Authority (S.M. Waszak), The University of Oslo (S.M. Waszak), NIH Grant CA192427 (J.E. Allen), Making Headway Foundation (S.L. Gardner), Gustave Roussy Foundation Pediatric Campaign (J. Grill), Imagine for Margo Charity (J. Grill), National Research Foundation of Korea (2022R1C1C1011998; C. Chung), Daegu Gyeongbuk Institute of Science and Technology (DGIST) Start-up Fund (2021050001; C. Chung), Taubman Institute, Michigan Medicine (S. Venneti), and NIH Grant U24-DK097153 (M. Kachman, H. Baum, and C.F. Burant). Publisher Copyright: {\textcopyright} 2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = nov,

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 (AACR)",

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

N1 - Funding Information: S.M. Waszak reports grants from The Research Council of Norway, the University of Oslo, and The South-Eastern Norway Regional Health Authority during the conduct of the study. R.S. Tarapore reports other support from Chimerix during the conduct of the study; other support from Chimerix outside the submitted work; and is an employee and stockholder of Chimerix S. Ramage reports personal fees from Chimerix during the conduct of the study, as well as other support from Chimerix outside the submitted work. A. Chi reports other support from Bright Peak Therapeutics and Mirati Therapeutics outside the submitted work, as well as a patent for methods for treatment of lung cancers pending. P.Y. Wen reports personal fees and other support from Chimerix during the conduct of the study. I. Arrillaga-Romany reports personal fees from Boehringer Ingelheim, and grants from Astex Pharmaceuticals and GSK outside the submitted work. T.T. Batchelor reports grants from ONO and the NIH, and personal fees from UpToDate outside the submitted work. A. Sumrall reports grants from Chimerix during the conduct of the study. R.A. Harrison reports other support from Pfizer and EMD Serono outside the submitted work. J. de Groot reports personal fees from Chimerix during the conduct of the study. M. Mehta reports other support from Oncoceutics and Chimerix during the conduct of the study, as well as personal fees from Kazia, Novocure, Zap, Xoft, Karyopharm, and Sapience outside the submitted work. M.D. Hall is a Voting Member, Proton Collaborative Group Executive Council (unpaid); treasurer, Proton Therapy Cooperative Group of North America (unpaid); cochair, Pediatric Subcommittee, Proton Therapy Cooperative Group (unpaid); and Radiation Oncology Study Committee Member, Children’s Oncology Group ACCL2031, ACNS2021, and ACNS2321 studies (unpaid). T.F. Cloughesy reports personal fees from Chimerix during the conduct of the study; personal fees from Katmai Pharmaceuticals, Erasca, Servier, Global Coalition for Adaptive Research, Roche, Sapience, Venrock, Blue Rock, Vida, Lista Therapeutics, Novartis, Kiyetic, Stemline, Break Through Cancer, Kintara, Ideology Health, COO, Sonalasence, Sagimet, Reovirus, Agios, Boehringer Ingelheim, VBL, Novocure, and Jubilant outside the submitted work; patent 11,377,451 issued, licensed, and with royalties paid from Katmai; and that The Regents of the University of California (T.F. Cloughesy employer) has licensed intellectual property coinvented by T.F. Cloughesy to Katmai Pharmaceuticals. B.M. Ellingson reports personal fees from MedQIA during the conduct of the study, as well as personal fees from Medicenna, Servier, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Monteris, Alpheus Medical, Curtana Pharma, Sagimet Biosciences, Sapience Therapeutics, Carthera, Imaging Endpoints, and Orbus Therapeutics, and grants and personal fees from Siemens and Neosoma outside the submitted work. Y. Umemura reports grants from Chimerix during the conduct of the study, as well as grants from Chimerix, Servier, ONO Pharmaceutical, and Gateway for Cancer Research, and personal fees from Tempus outside the submitted work. A. Franson reports other support from Day One Biotherapeutics outside the submitted work. N. Agar reports nonfinancial support from Bruker and Thermo Fisher, and other support from EMD Serono outside the submitted work. J. Grill reports nonfinancial support from Chimerix during the conduct of the study. C. Kline reports nonfinancial support and other support from Oncoceutics/Chimerix during the conduct of the study, as well as nonfinancial support and other support from Bristol Myers Squibb, Curis, Midatech, Kazia, Day One Biopharmaceuticals, and Regeneron outside the submitted work. J.E. Allen reports other support from Chimerix during the conduct of the study, as well as a patent for ONC201 and imipridones pending, issued, licensed, and with royalties paid from Chimerix. Y. Odia reports grants from Chi-merix during the conduct of the study. S.L. Gardner reports grants from the Making Headway Foundation during the conduct of the study. No disclosures were reported by the other authors. Funding Information: The authors thank the patients and their families for participating in this study. This study was financially supported by NIH grant R01-NS119231 (C. Koschmann), NIH grant R01-NS124607 (C. Koschmann), NIH grant R01-NS110572 (S. Venneti), NIH grant R01-CA261926 (S. Venneti), DOD grant CA201129P1 (C. Koschmann), University of Michigan Chad Carr Pediatric Brain Tumor Center (C. Koschmann and S. Venneti), The Evans Family (C. Koschmann), ChadTough Defeat DIPG Foundation (C. Koschmann, S. Venneti, M. Mota, and C. Chung), the Al Musella Foundation (C. Koschmann), Catching Up with Jack (C. Koschmann), Pediatric Brain Tumor Foundation (C. Koschmann), Prayers from Maria Foundation (C. Koschmann), Michael Miller Memorial Foundation (C. Koschmann), Morgan Behen Golf Classic (C. Koschmann), Yuvaan Tiwari Foundation (C. Koschmann), Sontag Foundation (S. Venneti), Alex’s Lemonade Stand Foundation (S. Venneti), Hyundai Hope Foundation (S. Venneti), NIH Clinical Sequencing Exploratory Research Award Grant 1UM1HG006508 for PEDS-MIONCOSEQ Study (A. Chinnaiyan), Research Council of Norway 187615 (S.M. Waszak), The South-Eastern Norway Regional Health Authority (S.M. Waszak), The University of Oslo (S.M. Waszak), NIH Grant CA192427 (J.E. Allen), Making Headway Foundation (S.L. Gardner), Gustave Roussy Foundation Pediatric Campaign (J. Grill), Imagine for Margo Charity (J. Grill), National Research Foundation of Korea (2022R1C1C1011998; C. Chung), Daegu Gyeongbuk Institute of Science and Technology (DGIST) Start-up Fund (2021050001; C. Chung), Taubman Institute, Michigan Medicine (S. Venneti), and NIH Grant U24-DK097153 (M. Kachman, H. Baum, and C.F. Burant). Publisher Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.

PY - 2023/11

Y1 - 2023/11

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 - http://www.scopus.com/inward/record.url?scp=85173862801&partnerID=8YFLogxK

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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