Skip to main content
SpringerLink
Log in

Epigenetic-Targeted Treatments for H3K27M-Mutant Midline Gliomas

  • Chapter
  • First Online:
Histone Mutations and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1283))

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a lethal midline brainstem tumor that most commonly occurs in children and is genetically defined by substitution of methionine for lysine at site 27 of histone 3 (H3K27M) in the majority of cases. This mutation has since been shown to exert an influence on the posttranslational epigenetic landscape of this disease, with the loss of trimethylation at lysine 27 (H3K27me3) the most common alteration. Based on these findings, a number of drugs targeting these epigenetic changes have been proposed, specifically that alter histone trimethylation, acetylation, or phosphorylation. Various mechanisms have been explored, including inhibition of H327 demethylase and methyltransferase to target trimethylation, inhibition of histone deacetylase (HDAC) and bromodomain and extraterminal (BET) to target acetylation, and inhibition of phosphatase-related enzymes to target phosphorylation. This chapter reviews the current rationales and progress made to date in epigenetically targeting DIPG via these mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Louis DN et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  Google Scholar 

  2. van Zanten SEV et al (2017) Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease. J Neuro Oncol 132:255–266. https://doi.org/10.1007/s11060-016-2363-y

    Article  Google Scholar 

  3. Merchant TE, Pollack IF, Loeffler JS (2010) Brain tumors across the age spectrum: biology, therapy, and late effects. Semin Radiat Oncol 20:58–66. https://doi.org/10.1016/j.semradonc.2009.09.005

    Article  Google Scholar 

  4. de Blank PM et al (2015) Years of life lived with disease and years of potential life lost in children who die of cancer in the United States, 2009. Cancer Med 4:608–619. https://doi.org/10.1002/cam4.410

    Article  Google Scholar 

  5. Wu G et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253. https://doi.org/10.1038/ng.1102

    Article  CAS  Google Scholar 

  6. Castel D et al (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827. https://doi.org/10.1007/s00401-015-1478-0

    Article  CAS  Google Scholar 

  7. Lu VM, Alvi MA, McDonald KL, Daniels DJ (2018) Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis. J Neurosurg Pediatr:1–9. https://doi.org/10.3171/2018.9.Peds18419

  8. Castel D et al (2018) Transcriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location. Acta Neuropathol Commun 6:117. https://doi.org/10.1186/s40478-018-0614-1

    Article  CAS  Google Scholar 

  9. Fang D et al (2018) H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers. eLife 7. https://doi.org/10.7554/eLife.36696

  10. Vanan MI, Eisenstat DD (2015) DIPG in children – what can we learn from the past? Front Oncol 5:237. https://doi.org/10.3389/fonc.2015.00237

    Article  Google Scholar 

  11. Funato K, Major T, Lewis PW, Allis CD, Tabar V (2014) Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346:1529–1533. https://doi.org/10.1126/science.1253799

    Article  CAS  Google Scholar 

  12. Churchman LS, Weissman JS (2011) Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature 469:368–373. https://doi.org/10.1038/nature09652

    Article  CAS  Google Scholar 

  13. Hodges C, Bintu L, Lubkowska L, Kashlev M, Bustamante C (2009) Nucleosomal fluctuations govern the transcription dynamics of RNA polymerase II. Science 325:626–628. https://doi.org/10.1126/science.1172926

    Article  CAS  Google Scholar 

  14. Furey TS, Sethupathy P (2013) Genetics. Genetics driving epigenetics. Science 342:705–706. https://doi.org/10.1126/science.1246755

    Article  CAS  Google Scholar 

  15. Chan K-M et al (2013) The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 27:985–990. https://doi.org/10.1101/gad.217778.113

    Article  CAS  Google Scholar 

  16. Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C (2014) Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 128:573–581. https://doi.org/10.1007/s00401-014-1319-6

    Article  CAS  Google Scholar 

  17. Pathak P et al (2015) Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM. J Neuro-Oncol 121:489–497. https://doi.org/10.1007/s11060-014-1675-z

    Article  CAS  Google Scholar 

  18. Hashizume R (2017) Epigenetic targeted therapy for diffuse intrinsic pontine glioma. Neurol Med Chir 57:331–342. https://doi.org/10.2176/nmc.ra.2017-0018

    Article  Google Scholar 

  19. Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7:473–483. https://doi.org/10.1038/nrm1960

    Article  CAS  Google Scholar 

  20. Maury E, Hashizume R (2017) Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: insight into epigenetic therapies. Epigenetics 12:353–369. https://doi.org/10.1080/15592294.2016.1278095

    Article  Google Scholar 

  21. Silveira AB et al (2019) H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo. Acta Neuropathol 137:637–655. https://doi.org/10.1007/s00401-019-01975-4

    Article  CAS  Google Scholar 

  22. Venneti S et al (2013) Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 23:558–564. https://doi.org/10.1111/bpa.12042

    Article  CAS  Google Scholar 

  23. Piunti A et al (2017) Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 23:493–500. https://doi.org/10.1038/nm.4296

    Article  CAS  Google Scholar 

  24. Cao R et al (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298:1039–1043. https://doi.org/10.1126/science.1076997

    Article  CAS  Google Scholar 

  25. Lund AH, van Lohuizen M (2004) Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol 16:239–246. https://doi.org/10.1016/j.ceb.2004.03.010

    Article  CAS  Google Scholar 

  26. Agger K et al (2007) UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731–734. https://doi.org/10.1038/nature06145

    Article  CAS  Google Scholar 

  27. Kruidenier L et al (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–408. https://doi.org/10.1038/nature11262

    Article  CAS  Google Scholar 

  28. Hashizume R et al (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394–1396. https://doi.org/10.1038/nm.3716

    Article  CAS  Google Scholar 

  29. Ntziachristos P et al (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513–517. https://doi.org/10.1038/nature13605

    Article  CAS  Google Scholar 

  30. Bender S et al (2013) Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660–672. https://doi.org/10.1016/j.ccr.2013.10.006

    Article  CAS  Google Scholar 

  31. Mohammad F et al (2017) EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med 23:483–492. https://doi.org/10.1038/nm.4293

    Article  CAS  Google Scholar 

  32. Cordero FJ et al (2017) Histone H3.3K27M represses p16 to accelerate Gliomagenesis in a murine model of DIPG. Mol Cancer Res 15:1243–1254. https://doi.org/10.1158/1541-7786.Mcr-16-0389

    Article  CAS  Google Scholar 

  33. Knutson SK et al (2014) Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther 13:842. https://doi.org/10.1158/1535-7163.MCT-13-0773

    Article  CAS  Google Scholar 

  34. Verma SK et al (2012) Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett 3:1091–1096. https://doi.org/10.1021/ml3003346

    Article  CAS  Google Scholar 

  35. Wiese M et al (2016) No significant cytotoxic effect of the EZH2 inhibitor Tazemetostat (EPZ-6438) on pediatric glioma cells with wildtype histone 3 or mutated histone 3.3. Klinische Padiatr 228:113–117. https://doi.org/10.1055/s-0042-105292

    Article  CAS  Google Scholar 

  36. Bachmann IM et al (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24:268–273. https://doi.org/10.1200/jco.2005.01.5180

    Article  CAS  Google Scholar 

  37. Suva ML et al (2009) EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res 69:9211–9218. https://doi.org/10.1158/0008-5472.Can-09-1622

    Article  CAS  Google Scholar 

  38. Alimova I et al (2012) Targeting the enhancer of zeste homologue 2 in medulloblastoma. Int J Cancer 131:1800–1809. https://doi.org/10.1002/ijc.27455

    Article  CAS  Google Scholar 

  39. Krug B et al (2019) Pervasive H3K27 acetylation leads to ERV expression and a therapeutic vulnerability in H3K27M gliomas. Cancer Cell 35:782–797.e788. https://doi.org/10.1016/j.ccell.2019.04.004

    Article  CAS  Google Scholar 

  40. Kaelin WG Jr, McKnight SL (2013) Influence of metabolism on epigenetics and disease. Cell 153:56–69. https://doi.org/10.1016/j.cell.2013.03.004

    Article  CAS  Google Scholar 

  41. Filippakopoulos P, Knapp S (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13:337–356. https://doi.org/10.1038/nrd4286

    Article  CAS  Google Scholar 

  42. Lewis PW et al (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857–861. https://doi.org/10.1126/science.1232245

    Article  CAS  Google Scholar 

  43. Herz H-M et al (2014) Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling. Science 345:1065. https://doi.org/10.1126/science.1255104

    Article  CAS  Google Scholar 

  44. Grasso CS et al (2015) Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21:555–559. https://doi.org/10.1038/nm.3855

    Article  CAS  Google Scholar 

  45. Brown ZZ et al (2014) Strategy for "detoxification" of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2. J Am Chem Soc 136:13498–13501. https://doi.org/10.1021/ja5060934

    Article  CAS  Google Scholar 

  46. De Souza C, Chatterji BP (2015) HDAC inhibitors as novel anti-cancer therapeutics. Recent Pat Anticancer Drug Discov 10:145–162

    Google Scholar 

  47. Li Y, Seto E (2016) HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med 6. https://doi.org/10.1101/cshperspect.a026831

  48. Ellis L et al (2008) Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res 14:4500–4510. https://doi.org/10.1158/1078-0432.Ccr-07-4262

    Article  CAS  Google Scholar 

  49. Hennika T et al (2017) Pre-clinical study of Panobinostat in xenograft and genetically engineered murine diffuse intrinsic pontine glioma models. PLoS One 12:e0169485. https://doi.org/10.1371/journal.pone.0169485

    Article  CAS  Google Scholar 

  50. Thomas S et al (2016) A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma. Ann Oncol 27:947–952. https://doi.org/10.1093/annonc/mdw044

    Article  CAS  Google Scholar 

  51. Richardson P et al (2017) Treatment-free interval as a metric of patient experience and a health outcome of value for advanced multiple myeloma: the case for the histone deacetylase inhibitor panobinostat, a next-generation novel agent. Expert Rev Hematol 10:933–939. https://doi.org/10.1080/17474086.2017.1369399

    Article  CAS  Google Scholar 

  52. El-Khouly FE et al (2017) Effective drug delivery in diffuse intrinsic pontine glioma: a theoretical model to identify potential candidates. Front Oncol 7:254. https://doi.org/10.3389/fonc.2017.00254

    Article  Google Scholar 

  53. Marushige K (1976) Activation of chromatin by acetylation of histone side chains. Proc Natl Acad Sci U S A 73:3937–3941. https://doi.org/10.1073/pnas.73.11.3937

    Article  CAS  Google Scholar 

  54. Wadhwa E, Nicolaides T (2016) Bromodomain inhibitor review: Bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus 8:e620. https://doi.org/10.7759/cureus.620

    Article  Google Scholar 

  55. Qi J (2014) Bromodomain and extraterminal domain inhibitors (BETi) for cancer therapy: chemical modulation of chromatin structure. Cold Spring Harb Perspect Biol 6:a018663. https://doi.org/10.1101/cshperspect.a018663

    Article  CAS  Google Scholar 

  56. Zhang Y et al (2017) Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma. Cell Biosci 7:56. https://doi.org/10.1186/s13578-017-0184-0

    Article  CAS  Google Scholar 

  57. Gehani SS et al (2010) Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol Cell 39:886–900. https://doi.org/10.1016/j.molcel.2010.08.020

    Article  CAS  Google Scholar 

  58. Ruthenburg AJ, Allis CD, Wysocka J (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25:15–30. https://doi.org/10.1016/j.molcel.2006.12.014

    Article  CAS  Google Scholar 

  59. Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell 31:449–461. https://doi.org/10.1016/j.molcel.2008.07.002

    Article  CAS  Google Scholar 

  60. Schramm K et al (2019) DECIPHER pooled shRNA library screen identifies PP2A and FGFR signaling as potential therapeutic targets for DIPGs. Neuro-Oncology. https://doi.org/10.1093/neuonc/noz057

  61. Nowak SJ, Pai C-Y, Corces VG (2003) Protein phosphatase 2A activity affects histone H3 phosphorylation and transcription in Drosophila melanogaster. Mol Cell Biol 23:6129. https://doi.org/10.1128/MCB.23.17.6129-6138.2003

    Article  CAS  Google Scholar 

  62. Moreno L et al (2015) A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study. Clin Cancer Res 21:267–273. https://doi.org/10.1158/1078-0432.Ccr-14-1592

    Article  CAS  Google Scholar 

  63. Hake SB et al (2005) Serine 31 phosphorylation of histone variant H3.3 is specific to regions bordering centromeres in metaphase chromosomes. Proc Natl Acad Sci U S A 102:6344–6349. https://doi.org/10.1073/pnas.0502413102

    Article  CAS  Google Scholar 

  64. Figueroa JM et al (2017) Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro-Oncology 19:1494–1502. https://doi.org/10.1093/neuonc/nox085

    Article  CAS  Google Scholar 

  65. Wang Z et al (2015) MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma. Biomed Rep 3:543–548. https://doi.org/10.3892/br.2015.462

    Article  CAS  Google Scholar 

  66. Lu VM, Power EA, Zhang L, Daniels DJ (2019) Unlocking the translational potential of circulating nucleosomes for liquid biopsy in diffuse intrinsic pontine glioma. Biomark Med. https://doi.org/10.2217/bmm-2019-0139

  67. Gezer U et al (2015) Histone methylation Marks on circulating nucleosomes as novel blood-based biomarker in colorectal cancer. Int J Mol Sci 16:29654–29662. https://doi.org/10.3390/ijms161226180

    Article  CAS  Google Scholar 

  68. Syren P, Andersson R, Bauden M, Ansari D (2017) Epigenetic alterations as biomarkers in pancreatic ductal adenocarcinoma. Scand J Gastroenterol 52:668–673. https://doi.org/10.1080/00365521.2017.1301989

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA

    Victor M. Lu & David J. Daniels

Authors
  1. Victor M. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Daniels
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David J. Daniels .

Editor information

Editors and Affiliations

  1. Institute of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China

    Dong Fang

  2. State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China

    Junhong Han

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lu, V.M., Daniels, D.J. (2021). Epigenetic-Targeted Treatments for H3K27M-Mutant Midline Gliomas. In: Fang, D., Han, J. (eds) Histone Mutations and Cancer. Advances in Experimental Medicine and Biology, vol 1283. Springer, Singapore. https://doi.org/10.1007/978-981-15-8104-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation