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

View More View Less
  • 1 Departments of Radiation Oncology,
  • 3 Neurology, and
  • 7 Oncology, Miami Cancer Institute; Departments of
  • 2 Radiation Oncology,
  • 5 Pediatric Oncology, and
  • 6 Pediatric Neurosurgery, Nicklaus Children’s Hospital, Miami, Florida;
  • 4 Oncoceutics, Philadelphia, Pennsylvania; and
  • 8 NYU Langone Medical Center and School of Medicine, New York, New York
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

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 × 2.1 × 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.

ABBREVIATIONS DIPG = diffuse intrinsic pontine glioma; DR = dopamine receptor; IMRT = intensity-modulated radiotherapy; RECIST = Response Evaluation Criteria In Solid Tumors.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Matthew D. Hall: Miami Cancer Institute, Miami, FL. matthewha@baptisthealth.net.

INCLUDE WHEN CITING Published online April 5, 2019; DOI: 10.3171/2019.2.PEDS18480.

Disclosures J.E.A., R.T., L.S., and W.O. have ownership/employment relationships with Oncoceutics, which developed ONC201. M.P.M. serves on the Board of Directors of Oncoceutics (with stock options).

  • 1

    Allen JE, Kline CL, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, : Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget 7:7438074392, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, : Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med 5:171ra17, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Arrillaga-Romany I, Chi AS, Allen JE, Oster W, Wen PY, Batchelor TT: A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget 8:7929879304, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, : Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660672, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, : Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451456, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, : The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 27:985990, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Chi AS, Stafford JM, Sen N, Possemato R, Placantonakis D, Hidalgo ET, : H3 K27M mutant gliomas are selectively killed by ONC201, a small molecule inhibitor of dopamine receptor D2. Neuro Oncol 19:vi81, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, : Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21:555559, 2015

  • 9

    Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, : ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal 9:ra17, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Janssens GO, Jansen MH, Lauwers SJ, Nowak PJ, Oldenburger FR, Bouffet E, : Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiat Oncol Biol Phys 85:315320, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Jones C, Karajannis MA, Jones DTW, Kieran MW, Monje M, Baker SJ, : Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 19:153161, 2017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Justin N, Zhang Y, Tarricone C, Martin SR, Chen S, Underwood E, : Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nat Commun 7:11316, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, : K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439447, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Kline CLB, Van den Heuvel APJ, Allen JE, Prabhu VV, Dicker DT, El-Deiry WS: ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases. Sci Signal 9:ra18, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, : Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857861, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Li J, Zhu S, Kozono D, Ng K, Futalan D, Shen Y, : Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma. Oncotarget 5:882893, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, : The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803820, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Mandell LR, Kadota R, Freeman C, Douglass EC, Fontanesi J, Cohen ME, : There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 43:959964, 1999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, : EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med 23:483492, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Nagaraja S, Vitanza NA, Woo PJ, Taylor KR, Liu F, Zhang L, : Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell 31:635652, 652.e1–652.e6, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Prabhu VV, Lulla AR, Madhukar NS, Ralff MD, Zhao D, Kline CLB, : Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors. PLoS One 12:e0180541, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, : Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 149:12841297, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, : Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226231, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Stein MN, Bertino JR, Kaufman HL, Mayer T, Moss R, Silk A, : First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. Clin Cancer Res 23:41634169, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, : Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251253, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Wu G, Diaz AK, Paugh BS, Rankin SL, Ju B, Li Y, : The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444450, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 3039 1419 132
Full Text Views 671 197 14
PDF Downloads 423 121 12
EPUB Downloads 0 0 0