Update on Pediatric Brain Tumors: the Molecular Era and Neuro-immunologic Beginnings

Abstract

Purpose of Review

To provide an update on the current landscape of pediatric brain tumors and the impact of novel molecular insights on classification, diagnostics, and therapeutics.

Recent Findings

Scientific understanding of the genetic basis of central nervous system tumors has expanded rapidly over the last several years. The shift in classification of tumors to a molecularly based schema, accompanied by a growing number of early phase clinical trials of therapies aimed at inhibiting tumoral genetic and epigenetic programs, as well as those attempting to harness and magnify the immune response, has allowed a deeper pathophysiologic understanding of brain tumors and simultaneously provided opportunities for novel treatment.

Summary

Over the last 5 years, there has been tremendous growth in the field of pediatric neuro-oncology with increasing understanding of the genetic and epigenetic heterogeneity of CNS tumors. Attempts are underway to translate these insights into tumor-specific treatments.

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

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro-Oncology. 2013;15(SUPPL.2):1–56. https://doi.org/10.1093/neuonc/not151.

    Article  Google Scholar 

  2. 2.

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20. https://doi.org/10.1007/s00401-016-1545-1.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Nagaraja S, Vitanza NA, Woo PJ, Taylor KR, Liu F, Zhang L, et al. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell. 2017;31:635–652.e6.

    CAS  Article  Google Scholar 

  4. 4.

    Jones DTW, Gronych J, Lichter P, Witt O, Pfister SM. MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci. 2012;69(11):1799–811. https://doi.org/10.1007/s00018-011-0898-9.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD, et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 2016;131:833–45. https://doi.org/10.1007/s00401-016-1539-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med. 2016;375:2550–60. https://doi.org/10.1056/NEJMoa1605943.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    •• Banerjee, A., Jakacki, R. I., Onar-Thomas, A., Wu, S., Nicolaides, T., Young Poussaint, T., … Fouladi, M. (2017). A phase i trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro-Oncology. https://doi.org/10.1093/neuonc/now282. One of the first studies to describe the use of MEK-inhibitors for patients with low grade glioma.

  8. 8.

    Kondyli M, Larouche V, Saint-Martin C, Ellezam B, Pouliot L, Sinnett D, et al. Trametinib for progressive pediatric low-grade gliomas. J Neuro-Oncol. 2018;140:435–44. https://doi.org/10.1007/s11060-018-2971-9.

    CAS  Article  Google Scholar 

  9. 9.

    Dabrafenib Effective in Pediatric Glioma. (2017). In Cancer discovery. /https://doi.org/10.1158/2159-8290.CD-NB2016-140

  10. 10.

    Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20:1011–22. https://doi.org/10.1016/S1470-2045(19)30277-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N Engl J Med. 2017;377:1648–56. https://doi.org/10.1056/NEJMoa1703784.

    Article  PubMed  Google Scholar 

  12. 12.

    Stone TJ, Keeley A, Virasami A, Harkness W, Tisdall M, Izquierdo Delgado E, et al. Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathol. 2018;135:115–29. https://doi.org/10.1007/s00401-017-1773-z.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Baisden BL, Brat DJ, Melhem ER, Rosenblum MK, King AP, Burger PC. Dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum: a lesion often misdiagnosed as glioma: report of 10 cases. Am J Surg Pathol. 2001;25:494–9. https://doi.org/10.1097/00000478-200104000-00009.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Pekmezci M, Villanueva-Meyer JE, Goode B, Van Ziffle J, Onodera C, Grenert JP, et al. The genetic landscape of ganglioglioma. Acta Neuropathol Commun. 2018;6. https://doi.org/10.1186/s40478-018-0551-z.

  15. 15.

    Wang AC, Jones DTW, Abecassis IJ, Cole BL, Leary SES, Lockwood CM, et al. Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) are distinct entities with frequent BRAFV600 mutations. Mol Cancer Res. 2018;16:1491–8. https://doi.org/10.1158/1541-7786.MCR-17-0507.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Greer A, Foreman NK, Donson A, Davies KD, Kleinschmidt-DeMasters BK. Desmoplastic infantile astrocytoma/ganglioglioma with rare BRAF V600D mutation. Pediatric Blood and Cancer. 2017;64:e26350. https://doi.org/10.1002/pbc.26350.

    CAS  Article  Google Scholar 

  17. 17.

    Blessing, M. M., Blackburn, P. R., Krishnan, C., Harrod, V. L., Barr Fritcher, E. G., Zysk, C. D., … Ida, C. M. (2019). Desmoplastic infantile Ganglioglioma: A MAPK Pathway-Driven and Microglia/Macrophage-Rich Neuroepithelial Tumor. J Neuropathol Exp Neurol. https://doi.org/10.1093/jnen/nlz086.

  18. 18.

    Sievers P, Appay R, Schrimpf D, Stichel D, Reuss DE, Wefers AK, et al. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol. 2019;138:497–504. https://doi.org/10.1007/s00401-019-02038-4.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Chiang JCH, Harreld JH, Orr BA, Sharma S, Ismail A, Segura AD, et al. Low-grade spinal glioneuronal tumors with BRAF gene fusion and 1p deletion but without leptomeningeal dissemination. Acta Neuropathol. 2017;134:159–62. https://doi.org/10.1007/s00401-017-1728-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Chiang J, Dalton J, Upadhyaya SA, Patay Z, Qaddoumi I, Li X, et al. Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion. Acta Neuropathol. 2019;137:179–81. https://doi.org/10.1007/s00401-018-1940-x.

    Article  PubMed  Google Scholar 

  21. 21.

    •• Schwartzentruber J, Korshunov A, Liu XY, Jones DTW, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012. https://doi.org/10.1038/nature10833The initial report of regulatory histone mutations involved in pediatric high grade glioma.

  22. 22.

    Sturm D, Bender S, Jones DTW, Lichter P, Grill J, Becher O, et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014;14:92–107. https://doi.org/10.1038/nrc3655.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Nagaraja S, Quezada MA, Gillespie SM, Arzt M, Lennon JJ, Woo PJ, et al. Histone variant and cell context determine H3K27M reprogramming of the enhancer landscape and oncogenic state. Mol Cell. 2019;76:965–980.e12.

    CAS  Article  Google Scholar 

  24. 24.

    Welby JP, Kaptzan T, Wohl A, Peterson TE, Raghunathan A, Brown DA, et al. Current murine models and new developments in H3K27M diffuse midline gliomas. Front Oncol. 2019.

  25. 25.

    Hennika T, Hu G, Olaciregui NG, Barton KL, Ehteda A, Chitranjan A, et al. Pre-clinical study of panobinostat in xenograft and genetically engineered murine diffuse intrinsic pontine glioma models. PLoS One. 2017;12:e0169485. https://doi.org/10.1371/journal.pone.0169485.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Singleton WGB, Bieneman AS, Woolley M, Johnson D, Lewis O, Wyatt MJ, et al. The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery. J Neurosurg Pediatr. 2018;22:288–96. https://doi.org/10.3171/2018.2.PEDS17663.

    Article  PubMed  Google Scholar 

  27. 27.

    Vitanza NA, Monje M. Diffuse intrinsic pontine Glioma: from diagnosis to next-generation clinical trials. Curr Treat Options Neurol. 2019. https://doi.org/10.1007/s11940-019-0577-y.

  28. 28.

    Pajtler KW, Mack SC, Ramaswamy V, Smith CA, Witt H, Smith A, et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol. 2017;133:5–12. https://doi.org/10.1007/s00401-016-1643-0.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31:737–754.e6. https://doi.org/10.1016/j.ccell.2017.05.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Pajtler KW, Wen J, Sill M, Lin T, Orisme W, Tang B, et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 2018;136:211–26. https://doi.org/10.1007/s00401-018-1877-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, et al. Medulloblastoma. Nat Rev Dis Primers. 2019;5. https://doi.org/10.1038/s41572-019-0063-6.

  32. 32.

    Archer TC, Mahoney EL, Pomeroy SL. Medulloblastoma: molecular classification-based personal therapeutics. Neurotherapeutics. 2017:265–73. https://doi.org/10.1007/s13311-017-0526-y.

  33. 33.

    •• Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012. https://doi.org/10.1007/s00401-011-0922-zThe initial consensus paper on four subgroups of medulloblastoma based on molecular classification.

  34. 34.

    Goschzik T, Schwalbe EC, Hicks D, Smith A, zur Muehlen, A., Figarella-Branger, D., … Clifford, S. C. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 2018;19:1602–16. https://doi.org/10.1016/S1470-2045(18)30532-1.

  35. 35.

    Northcott PA, Shih DJH, Peacock J, Garzia L, Sorana Morrissy A, Zichner T, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488:49–56. https://doi.org/10.1038/nature11327.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, et al. Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol. 2017;18:958–71. https://doi.org/10.1016/S1470-2045(17)30243-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M, et al. Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of group 3 and group 4 subtypes. Acta Neuropathol. 2019;138:309–26. https://doi.org/10.1007/s00401-019-02020-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Yeo KK, Margol AS, Kennedy RJ, Hung L, Robison NJ, Dhall G, et al. Prognostic significance of molecular subgroups of medulloblastoma in young children receiving irradiation-sparing regimens. J Neuro-Oncol. 2019;145:375–83.

    CAS  Article  Google Scholar 

  39. 39.

    Lafay-Cousin L, Smith A, Chi SN, Wells E, Madden J, Margol A, et al. Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy. Pediatric Blood Cancer. 2016;63:1527–34. https://doi.org/10.1002/pbc.26042.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al. Vismodegib exerts targeted efficacy against recurrent sonic hedgehog - subgroup medulloblastoma: results from phase II Pediatric Brain Tumor Consortium studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33:2646–54. https://doi.org/10.1200/JCO.2014.60.1591.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol. 2018;19:785–98. https://doi.org/10.1016/S1470-2045(18)30242-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Vladoiu MC, El-Hamamy I, Donovan LK, Farooq H, Holgado BL, Sundaravadanam Y, et al. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature. 2019;572:67–73.

    CAS  Article  Google Scholar 

  43. 43.

    Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw MKL, Baumgartner A, et al. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature. 2019;572:74–9. https://doi.org/10.1038/s41586-019-1434-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Hwang EI, Kool M, Burger PC, Capper D, Chavez L, Brabetz S, et al. Extensive molecular and clinical heterogeneity in patients with histologically diagnosed CNS-PNET treated as a single entity: a report from the children’s oncology group randomized ACNS0332 trial. J Clin Oncol. 2018;36:3388–95. https://doi.org/10.1200/JCO.2017.76.4720.

    CAS  Article  Google Scholar 

  45. 45.

    Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell. 2016;29:379–93. https://doi.org/10.1016/j.ccell.2016.02.001.

    CAS  Article  Google Scholar 

  46. 46.

    Fruhwald MC, Madsen PJ, Nemes K, Bens S, Steinbugl M, Johann PD, et al. Age and DNA-methylation subgroup as potential independent risk factors for treatment stratification in children with Atypical Teratoid/Rhabdoid Tumors (ATRT). Neuro-Oncology. 2019;(December). https://doi.org/10.1093/neuonc/noz244.

  47. 47.

    Foster JB, Madsen PJ, Hegde M, Ahmed N, Cole KA, Maris JM, et al. Immunotherapy for pediatric brain tumors: past and present. Neuro-Oncology. 2019;21(August):1226–38. https://doi.org/10.1093/neuonc/noz077.

    Article  PubMed  Google Scholar 

  48. 48.

    Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16:e534–42. https://doi.org/10.1016/S1470-2045(15)00088-1.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Potter DM, et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J Clin Oncol. 2014;32:2050–8. https://doi.org/10.1200/JCO.2013.54.0526.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Normolle DP, et al. Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro-Oncology. 2016;18:1157–68. https://doi.org/10.1093/neuonc/now026.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Lasky JL, Panosyan EH, Plant A, Davidson T, Yong WH, Prins RM, et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 2013.

  52. 52.

    Ochs K, Ott M, Bunse T, Sahm F, Bunse L, Deumelandt K, et al. K27M-mutant histone-3 as a novel target for glioma immunotherapy. OncoImmunology. 2017. https://doi.org/10.1080/2162402X.2017.1328340.

  53. 53.

    Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565:234–9. https://doi.org/10.1038/s41586-018-0792-9.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66(10):1249–64.

    CAS  Article  Google Scholar 

  55. 55.

    Tejada S, Alonso M, Patiño A, Fueyo J, Gomez-Manzano C, Diez-Valle R. Phase I trial of DNX-2401 for diffuse intrinsic pontine glioma newly diagnosed in pediatric patients. Neurosurgery. 2017.

  56. 56.

    Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology. 2018;20(5):674–86.

    CAS  Article  Google Scholar 

  57. 57.

    Majzner RG, Simon JS, Grosso JF, Martinez D, Pawel BR, Santi M, et al. Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues. Cancer. 2017;123(19):3807–15.

    CAS  Article  Google Scholar 

  58. 58.

    Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 2016;34(19):2206–11.

    CAS  Article  Google Scholar 

  59. 59.

    Chheda ZS, Kohanbash G, Okada K, Jahan N, Sidney J, Pecoraro M, et al. Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. J Exp Med. 2018;215(1):141–57.

    CAS  Article  Google Scholar 

  60. 60.

    Orlando D, Miele E, De Angelis B, et al. Adoptive immunotherapy using PRAME-specific T cells in medulloblastoma. Cancer Res. 2018;78(12):3337–49.

    CAS  PubMed  Google Scholar 

  61. 61.

    Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094–101.

    Article  Google Scholar 

  62. 62.

    Mount CW, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat Med. 2018;24(5):572–9.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Roger J. Packer.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuro-Oncology

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Duke, E.S., Packer, R.J. Update on Pediatric Brain Tumors: the Molecular Era and Neuro-immunologic Beginnings. Curr Neurol Neurosci Rep 20, 30 (2020). https://doi.org/10.1007/s11910-020-01050-6

Download citation

Keywords

  • Pediatric
  • Brain tumors
  • Neuro-oncology
  • Molecular
  • Immunotherapy
  • Targeted therapy