ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

Evangeline R. Jackson; Ryan J. Duchatel; Dilana E. Staudt; Mika L. Persson; Abdul Mannan; Sridevi Yadavilli; Sarah Parackal; Shaye Game; Wai Chin Chong; W. N. Samantha Jayasekara; Marion le Grand; Padraic S. Kearney; Alicia M. Douglas; Izac J. Findlay; Zacary P. Germon; Holly P. McEwen; Tyrone S. Beitaki; Adjanie Patabendige; David A. Skerrett-Byrne; Brett Nixon; Nathan D. Smith; Bryan Day; Neevika Manoharan; Sumanth Nagabushan; Jordan R. Hansford; Dinisha Govender; Geoff B. McCowage; Ron Firestein; Meegan Howlett; Raelene Endersby; Nicholas G. Gottardo; Frank Alvaro; Sebastian M. Waszak; Martin R. Larsen; Yolanda Colino-Sanguino; Fatima Valdes-Mora; Andria Rakotomalala; Samuel Meignan; Eddy Pasquier; Nicolas André; Esther Hulleman; David D. Eisenstat; Nicholas A. Vitanza; Javad Nazarian; Carl Koschmann; Sabine Mueller; Jason E. Cain; Matthew D. Dun

doi:https://doi.org/10.1158/0008-5472.CAN-23-0186

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

Evangeline R. Jackson, Ryan J. Duchatel, Dilana E. Staudt, Mika L. Persson, Abdul Mannan, Sridevi Yadavilli, Sarah Parackal, Shaye Game, Wai Chin Chong, W. N. Samantha Jayasekara, Marion le Grand, Padraic S. Kearney, Alicia M. Douglas, Izac J. Findlay, Zacary P. Germon, Holly P. McEwen, Tyrone S. Beitaki, Adjanie Patabendige, David A. Skerrett-Byrne, Brett NixonNathan D. Smith, Bryan Day, Neevika Manoharan, Sumanth Nagabushan, Jordan R. Hansford, Dinisha Govender, Geoff B. McCowage, Ron Firestein, Meegan Howlett, Raelene Endersby, Nicholas G. Gottardo, Frank Alvaro, Sebastian M. Waszak, Martin R. Larsen, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicolas André, Esther Hulleman, David D. Eisenstat, Nicholas A. Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E. Cain, Matthew D. Dun

Paediatric (VUmc)

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

7 Citations (Scopus)

Abstract

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Original language	English
Pages (from-to)	2421-2437
Number of pages	17
Journal	Cancer research
Volume	83
Issue number	14
DOIs	https://doi.org/10.1158/0008-5472.CAN-23-0186
Publication status	Published - 1 Jul 2023

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https://doi.org/10.1158/0008-5472.CAN-23-0186

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Jackson, E. R., Duchatel, R. J., Staudt, D. E., Persson, M. L., Mannan, A., Yadavilli, S., Parackal, S., Game, S., Chong, W. C., Jayasekara, W. N. S., le Grand, M., Kearney, P. S., Douglas, A. M., Findlay, I. J., Germon, Z. P., McEwen, H. P., Beitaki, T. S., Patabendige, A., Skerrett-Byrne, D. A., ... Dun, M. D. (2023). ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. Cancer research, 83(14), 2421-2437. https://doi.org/10.1158/0008-5472.CAN-23-0186

@article{4c55104fa8084e568c2b2bfe7e793e96,

title = "ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma",

abstract = "Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.",

author = "Jackson, {Evangeline R.} and Duchatel, {Ryan J.} and Staudt, {Dilana E.} and Persson, {Mika L.} and Abdul Mannan and Sridevi Yadavilli and Sarah Parackal and Shaye Game and Chong, {Wai Chin} and Jayasekara, {W. N. Samantha} and {le Grand}, Marion and Kearney, {Padraic S.} and Douglas, {Alicia M.} and Findlay, {Izac J.} and Germon, {Zacary P.} and McEwen, {Holly P.} and Beitaki, {Tyrone S.} and Adjanie Patabendige and Skerrett-Byrne, {David A.} and Brett Nixon and Smith, {Nathan D.} and Bryan Day and Neevika Manoharan and Sumanth Nagabushan and Hansford, {Jordan R.} and Dinisha Govender and McCowage, {Geoff B.} and Ron Firestein and Meegan Howlett and Raelene Endersby and Gottardo, {Nicholas G.} and Frank Alvaro and Waszak, {Sebastian M.} and Larsen, {Martin R.} and Yolanda Colino-Sanguino and Fatima Valdes-Mora and Andria Rakotomalala and Samuel Meignan and Eddy Pasquier and Nicolas Andr{\'e} and Esther Hulleman and Eisenstat, {David D.} and Vitanza, {Nicholas A.} and Javad Nazarian and Carl Koschmann and Sabine Mueller and Cain, {Jason E.} and Dun, {Matthew D.}",

note = "Funding Information: fellowship from the French ARC Foundation. S. Parackal is supported by a Children{\textquoteright}s Cancer Foundation/Hudson Institute Scholarship. W.C. Chong is supported by a Monash University Postgraduate Award. J.E. Cain is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF17014). N.G. Gottardo is supported by the Perth Children{\textquoteright}s Hospital Foundation Stan Perron Chair in Pediatric Oncology and Hematology. The authors would also like to acknowledge support from the Zero Childhood Cancer Initiative, Children{\textquoteright}s Cancer Foundation, and Bailey{\textquoteright}s Day. F. Valdes-Mora is supported by the Cancer Institute NSW Fellowship CDF181218. J.R. Hansford is supported through grants from the McClurg and Hospital Research Foundations. The clinical trial is supported by Mithil Prasad Foundation, ChadTough Defeat DIPG Foundation, and Storm the Heavens, the last also supporting S. Meignan. Proteomics was facilitated by N.D. Smith from The Analytical and Biomolecular Research Facility and The Academic and Research Computing Support (ARCS) team, within IT Services at the University of Newcastle, who provided high-performance computing (HPC) infrastructure for bioinformatics analyses. Histology services were provided by Funding Information: The authors acknowledge all children and their families diagnosed with DIPG. The authors thank Profs. Michelle Monje and Angel Carcaboso for their generous gift of their DIPG cell line models. M.D. Dun is supported by a ChadTough Defeat DIPG New Investigator Grant and an NHMRC Investigator Grant—GNT1173892. The contents of the published material are solely the responsibility of the research institutions involved or individual authors and do not reflect the views of NHMRC. This project was supported by the ChadTough Defeat DIPG Foundation, RUN DIPG Ltd., Strategic Group, McDonald Jones Foundation, Vinva Foundation, PNOC Foundation, Yuvaan Tiwari Foundation, Kiriwina Investments, The Kids{\textquoteright} Cancer Project, The DIPG Collaborative, including: The Cure Starts Now Foundation, The Cure Starts Now Australia, Brooke Healey Foundation, Wayland Villars Foundation, ChadTough Foundation, Aidan{\textquoteright}s Avengers, Austin Strong, Cure Brain Cancer, Jeffrey Thomas Hayden Foundation, Laurie{\textquoteright}s Love Foundation, Love Chloe Foundation, Musella Foundation, Pray Hope Believe, Reflections Of Grace, Storm the Heavens Fund, Aubreigh{\textquoteright}s Army, Whitley{\textquoteright}s Wishes, Ryan{\textquoteright}s Hope, Benny{\textquoteright}s World, The Isabella and Marcus Foundation, Lauren{\textquoteright}s Fight for Cure, Robert Connor Dawes Foundation, The Gold Hope Project, Julia Barbara Foundation, Lily Larue Foundation, American Childhood Cancer Organization, RUN DIPG, Gabriella{\textquoteright}s Smile Foundation, and Snapgrant.com, Charlie Teo Foundation, Little Legs Foundation, Tour de Cure, Fight on the Beaches, John Hunter Hospital Charitable Trust, Edie{\textquoteright}s Kindness Project, Liv Like A Unicorn Foundation, Maitland Cancer Appeal Committee Limited, BlackJack Pastoral Company, The Hirsch Family Funderpants, and the Hunter Medical Research Institute. Kazia Therapeutics provided funding to support personnel of M.D. Dun{\textquoteright}s laboratory. With thanks to the Isabella and Marcus Foundation, E.R. Jackson and S. Game are supported by the Miette Skiller Scholarship Fund (Josephine Dun and Elliot Gautsch Scholars, respectively), a sub-fund of the Australian Communities Foundation. E.R. Jackson is supported by an HCRA Scholarship. R.J. Duchatel is supported by a ChadTough Defeat DIPG Foundation Fellowship Grant. M. Le Grand, A. Rakotomalala, S. Meignan, and E. Pasquier received funding from “Association Wonder Augustine” and “Association Warrior Enguerrand” for their DIPG studies. M. Le Grand is supported by a postdoctoral fellowship from the French ARC Foundation. S. Parackal is supported by a Children{\textquoteright}s Cancer Foundation/Hudson Institute Scholarship. W.C. Chong is supported by a Monash University Postgraduate Award. J.E. Cain is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF17014). N.G. Gottardo is supported by the Perth Children{\textquoteright}s Hospital Foundation Stan Perron Chair in Pediatric Oncology and Hematology. The authors would also like to acknowledge support from the Zero Childhood Cancer Initiative, Children{\textquoteright}s Cancer Foundation, and Bailey{\textquoteright}s Day. F. Valdes-Mora is supported by the Cancer Institute NSW Fellowship CDF181218. J.R. Hansford is supported through grants from the McClurg and Hospital Research Foundations. The clinical trial is supported by Mithil Prasad Foundation, ChadTough Defeat DIPG Foundation, and Storm the Heavens, the last also supporting S. Meignan. Proteomics was facilitated by N.D. Smith from The Analytical and Biomolecular Research Facility and The Academic and Research Computing Support (ARCS) team, within IT Services at the University of Newcastle, who provided high-performance computing (HPC) infrastructure for bioinformatics analyses. Histology services were provided by Cassandra Griffin, Fiona Richards, Megan Clarke, and Kaylee O{\textquoteright}Brien from the HMRI Core Histology Facility. IHC optimization and staining services were provided by The University of Newcastle{\textquoteright}s “NSW Regional Biospecimen and Research Services,” with support from NSW Health Pathology. Funding Information: The authors acknowledge all children and their families diagnosed with DIPG. The authors thank Profs. Michelle Monje and Angel Carcaboso for their generous gift of their DIPG cell line models. M.D. Dun is supported by a ChadTough Defeat DIPG New Investigator Grant and an NHMRC Investigator Grant—GNT1173892. The contents of the published material are solely the responsibility of the research institutions involved or individual authors and do not reflect the views of NHMRC. This project was supported by the ChadTough Defeat DIPG Foundation, RUN DIPG Ltd., Strategic Group, McDonald Jones Foundation, Vinva Foundation, PNOC Foundation, Yuvaan Tiwari Foundation, Kiriwina Investments, The Kids{\textquoteright} Cancer Project, The DIPG Collaborative, including: The Cure Starts Now Foundation, The Cure Starts Now Australia, Brooke Healey Foundation, Wayland Villars Foundation, ChadTough Foundation, Aidan{\textquoteright}s Avengers, Austin Strong, Cure Brain Cancer, Jeffrey Thomas Hayden Foundation, Laurie{\textquoteright}s Love Foundation, Love Chloe Foundation, Musella Foundation, Pray Hope Believe, Reflections Of Grace, Storm the Heavens Fund, Aubreigh{\textquoteright}s Army, Whitley{\textquoteright}s Wishes, Ryan{\textquoteright}s Hope, Benny{\textquoteright}s World, The Isabella and Marcus Foundation, Lauren{\textquoteright}s Fight for Cure, Robert Connor Dawes Foundation, The Gold Hope Project, Julia Barbara Foundation, Lily Larue Foundation, American Childhood Cancer Organization, RUN DIPG, Gabriella{\textquoteright}s Smile Foundation, and Snapgrant.com, Charlie Teo Foundation, Little Legs Foundation, Tour de Cure, Fight on the Beaches, John Hunter Hospital Charitable Trust, Edie{\textquoteright}s Kindness Project, Liv Like A Unicorn Foundation, Maitland Cancer Appeal Committee Limited, BlackJack Pastoral Company, The Hirsch Family Funderpants, and the Hunter Medical Research Institute. Kazia Therapeutics provided funding to support personnel of M.D. Dun{\textquoteright}s laboratory. With thanks to the Isabella and Marcus Foundation, E.R. Jackson and S. Game are supported by the Miette Skiller Scholarship Fund (Josephine Dun and Elliot Gautsch Scholars, respectively), a sub-fund of the Australian Communities Foundation. E.R. Jackson is supported by an HCRA Scholarship. R.J. Duchatel is supported by a ChadTough Defeat DIPG Foundation Fellowship Grant. M. Le Grand, A. Rakotomalala, S. Meignan, and E. Pasquier received funding from “Association Wonder Augustine” and “Association Warrior Enguerrand” for their DIPG studies. M. Le Grand is supported by a postdoctoral Funding Information: A. Patabendige reports grants from NSW Ministry of Health, Australia and Hunter Medical Research Institute during the conduct of the study; as well as nonfinancial support from Pharmidex, UK and Flocel Inc. outside the submitted work. B. Day reports personal fees from Black Diamond Therapeutics, University of Sydney, and DC Europa outside the submitted work. J.R. Hansford reports personal fees from Bayer Australia, Boxer Capital, and Alexion Pharmaceuticals Australia outside the submitted work. R. Endersby reports other support from Cancer Council WA and Pirate Ship Foundation during the conduct of the study. N.G. Gottardo reports personal fees from Bayer, DayOne, and Eli Lily outside the submitted work. F. Alvaro reports personal fees from Norgine B.V. outside the submitted work. D.D. Eisenstat reports personal fees from Bayer Australia Ltd. outside the submitted work. M.D. Dun reports grants from Kazia Therapeutics during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright}2023 The Authors; Published by the American Association for Cancer Research.",

year = "2023",

month = jul,

day = "1",

doi = "https://doi.org/10.1158/0008-5472.CAN-23-0186",

language = "English",

volume = "83",

pages = "2421--2437",

journal = "Cancer research",

issn = "0008-5472",

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

number = "14",

}

Jackson, ER, Duchatel, RJ, Staudt, DE, Persson, ML, Mannan, A, Yadavilli, S, Parackal, S, Game, S, Chong, WC, Jayasekara, WNS, le Grand, M, Kearney, PS, Douglas, AM, Findlay, IJ, Germon, ZP, McEwen, HP, Beitaki, TS, Patabendige, A, Skerrett-Byrne, DA, Nixon, B, Smith, ND, Day, B, Manoharan, N, Nagabushan, S, Hansford, JR, Govender, D, McCowage, GB, Firestein, R, Howlett, M, Endersby, R, Gottardo, NG, Alvaro, F, Waszak, SM, Larsen, MR, Colino-Sanguino, Y, Valdes-Mora, F, Rakotomalala, A, Meignan, S, Pasquier, E, André, N, Hulleman, E, Eisenstat, DD, Vitanza, NA, Nazarian, J, Koschmann, C, Mueller, S, Cain, JE & Dun, MD 2023, 'ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma', Cancer research, vol. 83, no. 14, pp. 2421-2437. https://doi.org/10.1158/0008-5472.CAN-23-0186

TY - JOUR

T1 - ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

AU - Jackson, Evangeline R.

AU - Duchatel, Ryan J.

AU - Staudt, Dilana E.

AU - Persson, Mika L.

AU - Mannan, Abdul

AU - Yadavilli, Sridevi

AU - Parackal, Sarah

AU - Game, Shaye

AU - Chong, Wai Chin

AU - Jayasekara, W. N. Samantha

AU - le Grand, Marion

AU - Kearney, Padraic S.

AU - Douglas, Alicia M.

AU - Findlay, Izac J.

AU - Germon, Zacary P.

AU - McEwen, Holly P.

AU - Beitaki, Tyrone S.

AU - Patabendige, Adjanie

AU - Skerrett-Byrne, David A.

AU - Nixon, Brett

AU - Smith, Nathan D.

AU - Day, Bryan

AU - Manoharan, Neevika

AU - Nagabushan, Sumanth

AU - Hansford, Jordan R.

AU - Govender, Dinisha

AU - McCowage, Geoff B.

AU - Firestein, Ron

AU - Howlett, Meegan

AU - Endersby, Raelene

AU - Gottardo, Nicholas G.

AU - Alvaro, Frank

AU - Waszak, Sebastian M.

AU - Larsen, Martin R.

AU - Colino-Sanguino, Yolanda

AU - Valdes-Mora, Fatima

AU - Rakotomalala, Andria

AU - Meignan, Samuel

AU - Pasquier, Eddy

AU - André, Nicolas

AU - Hulleman, Esther

AU - Eisenstat, David D.

AU - Vitanza, Nicholas A.

AU - Nazarian, Javad

AU - Koschmann, Carl

AU - Mueller, Sabine

AU - Cain, Jason E.

AU - Dun, Matthew D.

N1 - Funding Information: fellowship from the French ARC Foundation. S. Parackal is supported by a Children’s Cancer Foundation/Hudson Institute Scholarship. W.C. Chong is supported by a Monash University Postgraduate Award. J.E. Cain is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF17014). N.G. Gottardo is supported by the Perth Children’s Hospital Foundation Stan Perron Chair in Pediatric Oncology and Hematology. The authors would also like to acknowledge support from the Zero Childhood Cancer Initiative, Children’s Cancer Foundation, and Bailey’s Day. F. Valdes-Mora is supported by the Cancer Institute NSW Fellowship CDF181218. J.R. Hansford is supported through grants from the McClurg and Hospital Research Foundations. The clinical trial is supported by Mithil Prasad Foundation, ChadTough Defeat DIPG Foundation, and Storm the Heavens, the last also supporting S. Meignan. Proteomics was facilitated by N.D. Smith from The Analytical and Biomolecular Research Facility and The Academic and Research Computing Support (ARCS) team, within IT Services at the University of Newcastle, who provided high-performance computing (HPC) infrastructure for bioinformatics analyses. Histology services were provided by Funding Information: The authors acknowledge all children and their families diagnosed with DIPG. The authors thank Profs. Michelle Monje and Angel Carcaboso for their generous gift of their DIPG cell line models. M.D. Dun is supported by a ChadTough Defeat DIPG New Investigator Grant and an NHMRC Investigator Grant—GNT1173892. The contents of the published material are solely the responsibility of the research institutions involved or individual authors and do not reflect the views of NHMRC. This project was supported by the ChadTough Defeat DIPG Foundation, RUN DIPG Ltd., Strategic Group, McDonald Jones Foundation, Vinva Foundation, PNOC Foundation, Yuvaan Tiwari Foundation, Kiriwina Investments, The Kids’ Cancer Project, The DIPG Collaborative, including: The Cure Starts Now Foundation, The Cure Starts Now Australia, Brooke Healey Foundation, Wayland Villars Foundation, ChadTough Foundation, Aidan’s Avengers, Austin Strong, Cure Brain Cancer, Jeffrey Thomas Hayden Foundation, Laurie’s Love Foundation, Love Chloe Foundation, Musella Foundation, Pray Hope Believe, Reflections Of Grace, Storm the Heavens Fund, Aubreigh’s Army, Whitley’s Wishes, Ryan’s Hope, Benny’s World, The Isabella and Marcus Foundation, Lauren’s Fight for Cure, Robert Connor Dawes Foundation, The Gold Hope Project, Julia Barbara Foundation, Lily Larue Foundation, American Childhood Cancer Organization, RUN DIPG, Gabriella’s Smile Foundation, and Snapgrant.com, Charlie Teo Foundation, Little Legs Foundation, Tour de Cure, Fight on the Beaches, John Hunter Hospital Charitable Trust, Edie’s Kindness Project, Liv Like A Unicorn Foundation, Maitland Cancer Appeal Committee Limited, BlackJack Pastoral Company, The Hirsch Family Funderpants, and the Hunter Medical Research Institute. Kazia Therapeutics provided funding to support personnel of M.D. Dun’s laboratory. With thanks to the Isabella and Marcus Foundation, E.R. Jackson and S. Game are supported by the Miette Skiller Scholarship Fund (Josephine Dun and Elliot Gautsch Scholars, respectively), a sub-fund of the Australian Communities Foundation. E.R. Jackson is supported by an HCRA Scholarship. R.J. Duchatel is supported by a ChadTough Defeat DIPG Foundation Fellowship Grant. M. Le Grand, A. Rakotomalala, S. Meignan, and E. Pasquier received funding from “Association Wonder Augustine” and “Association Warrior Enguerrand” for their DIPG studies. M. Le Grand is supported by a postdoctoral fellowship from the French ARC Foundation. S. Parackal is supported by a Children’s Cancer Foundation/Hudson Institute Scholarship. W.C. Chong is supported by a Monash University Postgraduate Award. J.E. Cain is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF17014). N.G. Gottardo is supported by the Perth Children’s Hospital Foundation Stan Perron Chair in Pediatric Oncology and Hematology. The authors would also like to acknowledge support from the Zero Childhood Cancer Initiative, Children’s Cancer Foundation, and Bailey’s Day. F. Valdes-Mora is supported by the Cancer Institute NSW Fellowship CDF181218. J.R. Hansford is supported through grants from the McClurg and Hospital Research Foundations. The clinical trial is supported by Mithil Prasad Foundation, ChadTough Defeat DIPG Foundation, and Storm the Heavens, the last also supporting S. Meignan. Proteomics was facilitated by N.D. Smith from The Analytical and Biomolecular Research Facility and The Academic and Research Computing Support (ARCS) team, within IT Services at the University of Newcastle, who provided high-performance computing (HPC) infrastructure for bioinformatics analyses. Histology services were provided by Cassandra Griffin, Fiona Richards, Megan Clarke, and Kaylee O’Brien from the HMRI Core Histology Facility. IHC optimization and staining services were provided by The University of Newcastle’s “NSW Regional Biospecimen and Research Services,” with support from NSW Health Pathology. Funding Information: The authors acknowledge all children and their families diagnosed with DIPG. The authors thank Profs. Michelle Monje and Angel Carcaboso for their generous gift of their DIPG cell line models. M.D. Dun is supported by a ChadTough Defeat DIPG New Investigator Grant and an NHMRC Investigator Grant—GNT1173892. The contents of the published material are solely the responsibility of the research institutions involved or individual authors and do not reflect the views of NHMRC. This project was supported by the ChadTough Defeat DIPG Foundation, RUN DIPG Ltd., Strategic Group, McDonald Jones Foundation, Vinva Foundation, PNOC Foundation, Yuvaan Tiwari Foundation, Kiriwina Investments, The Kids’ Cancer Project, The DIPG Collaborative, including: The Cure Starts Now Foundation, The Cure Starts Now Australia, Brooke Healey Foundation, Wayland Villars Foundation, ChadTough Foundation, Aidan’s Avengers, Austin Strong, Cure Brain Cancer, Jeffrey Thomas Hayden Foundation, Laurie’s Love Foundation, Love Chloe Foundation, Musella Foundation, Pray Hope Believe, Reflections Of Grace, Storm the Heavens Fund, Aubreigh’s Army, Whitley’s Wishes, Ryan’s Hope, Benny’s World, The Isabella and Marcus Foundation, Lauren’s Fight for Cure, Robert Connor Dawes Foundation, The Gold Hope Project, Julia Barbara Foundation, Lily Larue Foundation, American Childhood Cancer Organization, RUN DIPG, Gabriella’s Smile Foundation, and Snapgrant.com, Charlie Teo Foundation, Little Legs Foundation, Tour de Cure, Fight on the Beaches, John Hunter Hospital Charitable Trust, Edie’s Kindness Project, Liv Like A Unicorn Foundation, Maitland Cancer Appeal Committee Limited, BlackJack Pastoral Company, The Hirsch Family Funderpants, and the Hunter Medical Research Institute. Kazia Therapeutics provided funding to support personnel of M.D. Dun’s laboratory. With thanks to the Isabella and Marcus Foundation, E.R. Jackson and S. Game are supported by the Miette Skiller Scholarship Fund (Josephine Dun and Elliot Gautsch Scholars, respectively), a sub-fund of the Australian Communities Foundation. E.R. Jackson is supported by an HCRA Scholarship. R.J. Duchatel is supported by a ChadTough Defeat DIPG Foundation Fellowship Grant. M. Le Grand, A. Rakotomalala, S. Meignan, and E. Pasquier received funding from “Association Wonder Augustine” and “Association Warrior Enguerrand” for their DIPG studies. M. Le Grand is supported by a postdoctoral Funding Information: A. Patabendige reports grants from NSW Ministry of Health, Australia and Hunter Medical Research Institute during the conduct of the study; as well as nonfinancial support from Pharmidex, UK and Flocel Inc. outside the submitted work. B. Day reports personal fees from Black Diamond Therapeutics, University of Sydney, and DC Europa outside the submitted work. J.R. Hansford reports personal fees from Bayer Australia, Boxer Capital, and Alexion Pharmaceuticals Australia outside the submitted work. R. Endersby reports other support from Cancer Council WA and Pirate Ship Foundation during the conduct of the study. N.G. Gottardo reports personal fees from Bayer, DayOne, and Eli Lily outside the submitted work. F. Alvaro reports personal fees from Norgine B.V. outside the submitted work. D.D. Eisenstat reports personal fees from Bayer Australia Ltd. outside the submitted work. M.D. Dun reports grants from Kazia Therapeutics during the conduct of the study. No disclosures were reported by the other authors. Publisher Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

PY - 2023/7/1

Y1 - 2023/7/1

N2 - Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

AB - Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

UR - http://www.scopus.com/inward/record.url?scp=85166658340&partnerID=8YFLogxK

U2 - https://doi.org/10.1158/0008-5472.CAN-23-0186

DO - https://doi.org/10.1158/0008-5472.CAN-23-0186

M3 - Article

C2 - 37145169

SN - 0008-5472

VL - 83

SP - 2421

EP - 2437

JO - Cancer research

JF - Cancer research

IS - 14

ER -

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

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