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

被引：31

作者：

Jackson, Evangeline R. ^{[1
,2
]}

Duchatel, Ryan J. ^{[1
,2
]}

Staudt, Dilana E. ^{[1
,2
]}

Persson, Mika L. ^{[1
,2
]}

Mannan, Abdul ^{[1
,2
]}

Yadavilli, Sridevi ^{[3
,4
]}

Parackal, Sarah ^{[5
,6
]}

Game, Shaye ^{[5
,6
]}

Chong, Wai Chin ^{[5
,6
]}

Jayasekara, W. Samantha N. ^{[5
,6
]}

Le Grand, Marion ^{[7
]}

Kearney, Padraic S. ^{[1
,2
]}

Douglas, Alicia M. ^{[1
,2
]}

Findlay, Izac J. ^{[1
,2
]}

Germon, Zacary P. ^{[1
,2
]}

McEwen, Holly P. ^{[1
,2
]}

Beitaki, Tyrone S. ^{[1
,2
]}

Patabendige, Adjanie ^{[1
,8
,9
]}

Skerrett-Byrne, David A. ^{[10
,11
]}

Nixon, Brett ^{[10
,11
]}

Smith, Nathan D. ^{[12
]}

Day, Bryan ^{[13
]}

Manoharan, Neevika ^{[14
]}

Nagabushan, Sumanth ^{[14
]}

Hansford, Jordan R. ^{[15
]}

Govender, Dinisha ^{[16
]}

McCowage, Geoff B. ^{[16
]}

Firestein, Ron ^{[5
,6
]}

Howlett, Meegan ^{[17
]}

Endersby, Raelene ^{[17
]}

Gottardo, Nicholas G. ^{[17
,18
]}

Alvaro, Frank ^{[19
]}

Waszak, Sebastian M. ^{[20
,21
,22
]}

Larsen, Martin R. ^{[23
]}

Colino-Sanguino, Yolanda ^{[24
,25
]}

Valdes-Mora, Fatima ^{[24
,25
]}

Rakotomalala, Andria ^{[26
,27
]}

Meignan, Samuel ^{[26
,27
]}

Pasquier, Eddy ^{[7
,28
]}

Andre, Nicolas ^{[7
,28
,29
]}

Hulleman, Esther ^{[30
]}

Eisenstat, David D. ^{[31
,32
]}

Vitanza, Nicholas A. ^{[33
,34
]}

Nazarian, Javad ^{[3
,35
,36
]}

Koschmann, Carl ^{[37
]}

Mueller, Sabine ^{[35
,38
]}

Cain, Jason E. ^{[5
,6
]}

Dun, Matthew D. ^{[1
,2
,39
]}

机构：

[1] Univ Newcastle, Coll Hlth Med & Wellbeing, Sch Biomed Sci & Pharm, Canc Signalling Res Grp, Callaghan, NSW, Australia

[2] Hunter Med Res Inst, Precis Med Res Program, New Lambton Hts, NSW, Australia

[3] Childrens Natl Hosp, Ctr Genet Med Res, Washington, DC USA

[4] Childrens Natl Hosp, Brain Tumor Inst, Washington, DC USA

[5] Hudson Inst Med Res, Ctr Canc Res, Clayton, Vic, Australia

[6] Monash Univ, Dept Mol & Translat Sci, Clayton, Vic, Australia

[7] Aix Marseille Univ, Inst Paoli Calmettes, Ctr Rech Cancerol Marseille, CNRS,Inserm, Marseille, France

[8] Univ Newcastle, Coll Hlth Med & Wellbeing, Sch Biomed Sci & Pharm, Brain Barriers Grp, Callaghan, NSW, Australia

[9] Edge Hill Univ, Dept Biol, Ormskirk, England

[10] Univ Newcastle, Coll Engn Sci & Environm, Sch Environm & Life Sci, Callaghan, NSW, Australia

[11] Hunter Med Res Inst, Infertil & Reprod Res Program, New Lambton Hts, NSW, Australia

[12] Univ Newcastle, Analyt & Biomol Res Facil Adv Mass Spectrometry U, Callaghan, NSW, Australia

[13] QIMR Berghofer Med Res Inst, Herston, Qld, Australia

[14] Sydney Childrens Hosp, Dept Paediat Oncol, Randwick, NSW, Australia

[15] Univ Adelaide, Womens & Childrens Hosp, South Australia Hlth & Med Res Inst, South Australia ImmunoGen Canc Inst,Michael Rice, Adelaide, Australia

[16] Childrens Hosp Westmead, Dept Oncol, Westmead, NSW, Australia

[17] Univ Western Australia, Telethon Kids Inst, Telethon Kids Canc Ctr, Brain Tumor Res Program, Perth, Australia

[18] Perth Childrens Hosp, Dept Pediat & Adolescent Oncol & Hematol, Perth, Australia

[19] John Hunter Childrens Hosp, New Lambton Hts, NSW, Australia

[20] Univ Oslo, Ctr Mol Med Norway NCMM, Nord EMBL Partnership, Oslo, Norway

[21] Oslo Univ Hosp, Oslo, Norway

[22] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[23] Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark

[24] Childrens Canc Inst, Canc Epigenet Biol & Therapeut, Precis Med Theme, Sydney, NSW, Australia

[25] Univ NSW, Sch Womens & Childrens Hlth, Sydney, NSW, Australia

[26] Ctr Oscar Lambret, Tumorigenesis & Resistance Treatment Unit, Lille, France

[27] Univ Lille, Canc Heterogene Plast & Resistance Therapies, CANTHER, CHU Lille,CNRS,Inserm,UMR9020,U1277, Lille, France

[28] Metron Global Hlth Initiat, Marseille, France

[29] La Timone Childrens Hosp, AP HM, Dept Pediat Oncol, Marseille, France

[30] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[31] Royal Childrens Hosp Melbourne, Childrens Canc Ctr, Parkville, Vic, Australia

[32] Univ Melbourne, Murdoch Childrens Res Inst, Dept Paediat, Neurooncol Lab, Parkville, Vic, Australia

[33] Seattle Childrens Res Inst, Ben Towne Ctr Childhood Canc Res, Seattle, WA USA

[34] Seattle Childrens Hosp, Dept Pediat, Div Pediat Hematol Oncol, Seattle, WA USA

[35] Univ Childrens Hosp Zurich, Dept Pediat, Zurich, Switzerland

[36] George Washington Univ, Sch Med & Hlth Sci, Washington, DC USA

[37] Univ Michigan, Dept Pediat, Div Pediat Hematol Oncol, Ann Arbor, MI USA

[38] Univ Calif San Francisco, Dept Neurol Neurosurg & Pediat, San Francisco, CA USA

[39] Mark Hughes Fdn Ctr Brain Canc Res, Coll Hlth Med & Wellbeing, Paediat Program, Callaghan, NSW, Australia

来源：

CANCER RESEARCH | 2023年 / 83卷 / 14期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

PEDIATRIC HIGH-GRADE; H3.3K27M MUTATION; HISTONE H3.3; GROWTH; INHIBITORS; SURVIVAL; GDC-0084;

D O I：

10.1158/0008-5472.CAN-23-0186

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

◥ 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. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeo-stasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

引用

页码：2421 / 2437

页数：17

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