First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M-mutant pediatric diffuse intrinsic pontine glioma: a case report

被引：63

作者：

Hall, Matthew D. ^{[1
,4
]}

Odia, Yazmin ^{[2
]}

Allen, Joshua E. ^{[7
]}

Tarapore, Rohinton ^{[7
]}

Khatib, Ziad ^{[5
]}

Niazi, Toba N. ^{[6
]}

Daghistani, Doured ^{[3
]}

Schalop, Lee ^{[7
]}

Chi, Andrew S. ^{[8
,9
]}

Oster, Wolfgang ^{[7
]}

Mehta, Minesh P. ^{[1
]}

机构：

[1] Miami Canc Inst, Dept Radiat Oncol, Kendall, FL USA

[2] Miami Canc Inst, Dept Neurol, Kendall, FL USA

[3] Miami Canc Inst, Dept Oncol, Kendall, FL USA

[4] Nicklaus Childrens Hosp, Dept Radiat Oncol, Miami, FL USA

[5] Nicklaus Childrens Hosp, Dept Pediat Oncol, Miami, FL USA

[6] Nicklaus Childrens Hosp, Dept Pediat Neurosurg, Miami, FL USA

[7] Oncoceut, Philadelphia, PA USA

[8] NYU Langone Med Ctr, New York, NY USA

[9] Sch Med, New York, NY USA

来源：

JOURNAL OF NEUROSURGERY-PEDIATRICS | 2019年 / 23卷 / 06期

关键词：

diffuse intrinsic pontine glioma; diffuse midline glioma; targeted therapy; H3; K27M; DRD2; ONC201; oncology; INTEGRATED STRESS-RESPONSE; HISTONE H3.3; MUTATION; INHIBITION; SUBGROUPS; TARGET; TUMORS; TRIAL;

D O I：

10.3171/2019.2.PEDS18480

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M-mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M-mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary). The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 x 2.1 x 2.8-cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M-mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M-mutated DIPG.

引用

页码：719 / 725

页数：7

共 26 条

[1] Discovery and clinical introduction of first-in-class imipridone ONC201 [J].

Allen, Joshua E. ;

Kline, C. Leah B. ;

Prabhu, Varun V. ;

Wagner, Jessica ;

Ishizawa, Jo ;

Madhukar, Neel ;

Lev, Avital ;

Baumeister, Marie ;

Zhou, Lanlan ;

Lulla, Amriti ;

Stogniew, Martin ;

Schalop, Lee ;

Benes, Cyril ;

Kaufman, Howard L. ;

Pottorf, Richard S. ;

Nallaganchu, B. Rao ;

Olson, Gary L. ;

Al-Mulla, Fahd ;

Duvic, Madeleine ;

Wu, Gen Sheng ;

Dicker, David T. ;

Talekar, Mala K. ;

Lim, Bora ;

Elemento, Olivier ;

Oster, Wolfgang ;

Bertino, Joseph ;

Flaherty, Keith ;

Wang, Michael L. ;

Borthakur, Gautam ;

Andreeff, Michael ;

Stein, Mark ;

El-Deiry, Wafik S. .

ONCOTARGET, 2016, 7 (45) :74380-74392

[2] Dual Inactivation of Akt and ERK by TIC10 Signals Foxo3a Nuclear Translocation, TRAIL Gene Induction, and Potent Antitumor Effects [J].

Allen, Joshua E. ;

Krigsfeld, Gabriel ;

Mayes, Patrick A. ;

Patel, Luv ;

Dicker, David T. ;

Patel, Akshal S. ;

Dolloff, Nathan G. ;

Messaris, Evangelos ;

Scata, Kimberly A. ;

Wang, Wenge ;

Zhou, Jun-Ying ;

Wu, Gen Sheng ;

El-Deiry, Wafik S. .

SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (171)

[3] A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma [J].

Arrillaga-Romany, Isabel ;

Chi, Andrew S. ;

Allen, Joshua E. ;

Oster, Wolfgang ;

Wen, Patrick Y. ;

Batchelor, Tracy T. .

ONCOTARGET, 2017, 8 (45) :79298-79304

[4] Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas [J].

Bender, Sebastian ;

Tang, Yujie ;

Lindroth, Anders M. ;

Hovestadt, Volker ;

Jones, David T. W. ;

Kool, Marcel ;

Zapatka, Marc ;

Northcott, Paul A. ;

Sturm, Dominik ;

Wang, Wei ;

Radlwimmer, Bernhard ;

Hojfeldt, Jonas W. ;

Truffaux, Nathalene ;

Castel, David ;

Schubert, Simone ;

Ryzhova, Marina ;

Seker-Cin, Huriye ;

Gronych, Jan ;

Johann, Pascal David ;

Stark, Sebastian ;

Meyer, Jochen ;

Milde, Till ;

Schuhmann, Martin ;

Ebinger, Martin ;

Monoranu, Camelia-Maria ;

Ponnuswami, Anitha ;

Chen, Spenser ;

Jones, Chris ;

Witt, Olaf ;

Collins, V. Peter ;

von Deimling, Andreas ;

Jabado, Nada ;

Puget, Stephanie ;

Grill, Jacques ;

Helin, Kristian ;

Korshunov, Andrey ;

Lichter, Peter ;

Monje, Michelle ;

Plass, Christoph ;

Cho, Yoon-Jae ;

Pfister, Stefan M. .

CANCER CELL, 2013, 24 (05) :660-672

[5] Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations [J].

Buczkowicz, Pawel ;

Hoeman, Christine ;

Rakopoulos, Patricia ;

Pajovic, Sanja ;

Letourneau, Louis ;

Dzamba, Misko ;

Morrison, Andrew ;

Lewis, Peter ;

Bouffet, Eric ;

Bartels, Ute ;

Zuccaro, Jennifer ;

Agnihotri, Sameer ;

Rya, Scott ;

Barszczyk, Mark ;

Chornenkyy, Yevgen ;

Bourgey, Mathieu ;

Bourque, Guillaume ;

Montpetit, Alexandre ;

Cordero, Francisco ;

Castelo-Branco, Pedro ;

Mangere, Joshua ;

Tabori, Uri ;

Ching, King ;

Huang, Annie ;

Taylor, Kathryn R. ;

Mackay, Alan ;

Bendell, Anne E. ;

Nazarian, Javad ;

Fangusaro, Jason R. ;

Karajannis, Matthias A. ;

Zagzag, David ;

Foreman, Nicholas K. ;

Donson, Andrew ;

Hegert, Julia V. ;

Smith, Amy ;

Chan, Jennifer ;

Lafay-Cousin, Lucy ;

Dunn, Sandra ;

Hukin, Juliette ;

Dunham, Chris ;

Scheinemann, Katrin ;

Michaud, Jean ;

Zelcer, Shayna ;

Ramsay, David ;

Cain, Jason ;

Brennan, Cameron ;

Souweidane, Mark M. ;

Jones, Chris ;

Allis, C. David ;

Brudno, Michael .

NATURE GENETICS, 2014, 46 (05) :451-456

[6] The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression [J].

Chan, Kui-Ming ;

Fang, Dong ;

Gan, Haiyun ;

Hashizume, Rintaro ;

Yu, Chuanhe ;

Schroeder, Mark ;

Gupta, Nalin ;

Mueller, Sabine ;

James, C. David ;

Jenkins, Robert ;

Sarkaria, Jann ;

Zhang, Zhiguo .

GENES & DEVELOPMENT, 2013, 27 (09) :985-990

[7]

Chi AS, 2017, NEURO-ONCOLOGY, V19, P81

[8] K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas [J].

Dong-Anh Khuong-Quang ;

Buczkowicz, Pawel ;

Rakopoulos, Patricia ;

Liu, Xiao-Yang ;

Fontebasso, Adam M. ;

Bouffet, Eric ;

Bartels, Ute ;

Albrecht, Steffen ;

Schwartzentruber, Jeremy ;

Letourneau, Louis ;

Bourgey, Mathieu ;

Bourque, Guillaume ;

Montpetit, Alexandre ;

Bourret, Genevieve ;

Lepage, Pierre ;

Fleming, Adam ;

Lichter, Peter ;

Kool, Marcel ;

von Deimling, Andreas ;

Sturm, Dominik ;

Korshunov, Andrey ;

Faury, Damien ;

Jones, David T. ;

Majewski, Jacek ;

Pfister, Stefan M. ;

Jabado, Nada ;

Hawkins, Cynthia .

ACTA NEUROPATHOLOGICA, 2012, 124 (03) :439-447

[9] Functionally defined therapeutic targets in diffuse intrinsic pontine glioma [J].

Grasso, Catherine S. ;

Tang, Yujie ;

Truffaux, Nathalene ;

Berlow, Noah E. ;

Liu, Lining ;

Debily, Marie-Anne ;

Quist, Michael J. ;

Davis, Lara E. ;

Huang, Elaine C. ;

Woo, Pamelyn J. ;

Ponnuswami, Anitha ;

Chen, Spenser ;

Johung, Tessa B. ;

Sun, Wenchao ;

Kogiso, Mari ;

Dui, Yuchen ;

Qi, Lin ;

Huang, Yulun ;

Huett-Cabezas, Marianne ;

Warrenm, Katherine E. ;

Le Dret, Ludivine ;

Meltzerm, Paul S. ;

Mao, Hua ;

Quezado, Martha ;

van Vuurden, Dannis G. ;

Abraham, Jinu ;

Fouladi, Maryam ;

Svalina, Matthew N. ;

Wang, Nicholas ;

Hawkins, Cynthia ;

Nazarian, Javad ;

Alonso, Marta M. ;

Raabe, Eric H. ;

Hulleman, Esther ;

Spellman, Paul T. ;

Li, Xiao-Nan ;

Keller, Charles ;

Pal, Ranadip ;

Grill, Jacques ;

Monje, Michelle .

NATURE MEDICINE, 2015, 21 (06) :555-559

[10] ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies [J].

Ishizawa, Jo ;

Kojima, Kensuke ;

Chachad, Dhruv ;

Ruvolo, Peter ;

Ruvolo, Vivian ;

Jacamo, Rodrigo O. ;

Borthakur, Gautam ;

Mu, Hong ;

Zeng, Zhihong ;

Tabe, Yoko ;

Allen, Joshua E. ;

Wang, Zhiqiang ;

Ma, Wencai ;

Lee, Hans C. ;

Orlowski, Robert ;

Sarbassov, Dos D. ;

Lorenzi, Philip L. ;

Huang, Xuelin ;

Neelapu, Sattva S. ;

McDonnell, Timothy ;

Miranda, Roberto N. ;

Wang, Michael ;

Kantarjian, Hagop ;

Konopleva, Marina ;

Davis, R. Eric ;

Andreeff, Michael .

SCIENCE SIGNALING, 2016, 9 (415)

← 1 2 3 →