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Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas

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Abstract

Despite numerous clinical trials over the past 2 decades, the overall survival for children diagnosed with diffuse intrinsic pontine glioma (DIPG) remains 9–10 months. Radiation therapy is the only treatment with proven effect and novel therapies are needed. Epidermal growth factor receptor variant III (EGFRvIII) is the most common variant of the epidermal growth factor receptor and is expressed in many tumor types but is rarely found in normal tissue. A peptide vaccine targeting EGFRvIII is currently undergoing investigation in phase 3 clinical trials for the treatment of newly diagnosed glioblastoma (GBM), the tumor in which this variant receptor was first discovered. In this study, we evaluated EGFRvIII expression in pediatric DIPG samples using immunohistochemistry with a double affinity purified antibody raised against the EGFRvIII peptide. Staining of pediatric DIPG histological samples revealed expression in 4 of 9 cases and the pattern of staining was consistent with what has been seen in EGFRvIII transfected cells as well as GBMs from adult trials. In addition, analysis of tumor samples collected immediately post mortem and of DIPG cells in culture by RT-PCR, western blot analysis, and flow cytometry confirmed EGFRvIII expression. We were therefore able to detect EGFRvIII expression in 6 of 11 DIPG cases. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors.

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References

  1. Central brain tumor registry of the United States, (in 2009)

  2. Freeman CR, Farmer JP (1998) Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys 40(2):265

    Article  PubMed  CAS  Google Scholar 

  3. Recinos PF, Sciubba DM, Jallo GI (2007) Brainstem tumors: where are we today? Pediatr Neurosurg 43(3):192

    Article  PubMed  Google Scholar 

  4. Bernier-Chastagner V et al (2005) Topotecan as a radiosensitizer in the treatment of children with malignant diffuse brainstem gliomas: results of a French Society of Paediatric Oncology Phase II Study. Cancer 104(12):2792

    Article  PubMed  CAS  Google Scholar 

  5. Korones DN et al (2008) Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: a Children’s Oncology Group phase II study. Pediatr Blood Cancer 50(2):227

    Article  PubMed  Google Scholar 

  6. Mandell LR et al (1999) 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(5):959

    Article  PubMed  CAS  Google Scholar 

  7. Packer RJ et al (1994) Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer 74(6):1827

    Article  PubMed  CAS  Google Scholar 

  8. Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7(3):241

    Article  PubMed  Google Scholar 

  9. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341

    Article  PubMed  CAS  Google Scholar 

  10. Libermann TA et al (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313(5998):144

    Article  PubMed  CAS  Google Scholar 

  11. Wong AJ et al (1987) Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84(19):6899

    Article  PubMed  CAS  Google Scholar 

  12. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358(11):1160

    Article  PubMed  CAS  Google Scholar 

  13. Moscatello DK et al (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55(23):5536

    PubMed  CAS  Google Scholar 

  14. Humphrey PA et al (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87(11):4207

    Article  PubMed  CAS  Google Scholar 

  15. Wong AJ et al (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89(7):2965

    Article  PubMed  CAS  Google Scholar 

  16. Bax DA et al (2009) EGFRvIII deletion mutations in pediatric high-grade glioma and response to targeted therapy in pediatric glioma cell lines. CLin Cancer Res 15(18):5753

    Article  PubMed  CAS  Google Scholar 

  17. Li G, Wong AJ (2008) EGF receptor variant III as a target antigen for tumor immunotherapy Expert. Rev Vaccines 7(7):977

    Article  Google Scholar 

  18. Heimberger AB et al (2003) Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 9(11):4247

    PubMed  CAS  Google Scholar 

  19. Moscatello DK, Ramirez G, Wong AJ (1997) A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res 57(8):1419

    PubMed  CAS  Google Scholar 

  20. Sampson JH et al. (2008) Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM. In: American society of clinical oncology 26, Chicago

  21. Sampson JH et al (2008) Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 20(5):267

    Article  PubMed  CAS  Google Scholar 

  22. Schmittling RJ et al (2008) Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods 339(1):74

    Article  PubMed  CAS  Google Scholar 

  23. Gilbertson RJ et al (2003) ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. CLin Cancer Res 9(10 Pt 1):3620

    PubMed  CAS  Google Scholar 

  24. Monje M et al (2011) Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci USA 108(11):4453

    Article  PubMed  CAS  Google Scholar 

  25. Li Gordon et al (2010) Pineal parenchymal tumor of intermediate differentiation: clinicopathologic report and evaluation of epidermal growth factor receptor variant III expression. Neurosurgery 66(5):963–968

    Article  PubMed  Google Scholar 

  26. Moscatello DK et al (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55(23):5536

    PubMed  CAS  Google Scholar 

  27. Okamoto I et al (2003) Expression of constitutively activated EGFRvIII in non-small cell lung cancer. Cancer Sci 94(1):50

    Article  PubMed  CAS  Google Scholar 

  28. Guerrero-Cazares H, Chaichana KL, Quinones-Hinojosa A (2009) Neurosphere culture and human organotypic model to evaluate brain tumor stem cells. Methods Mol Biol 568:73–83

    Article  PubMed  Google Scholar 

  29. Bullain SS et al (2009) Genetically engineered T cells to target EGFRvIII expressing glioblastoma. J Neurooncol 94(3):373

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

We would like to acknowledge Dr. David Louis and Dr. Keith Ligon for providing the paraffin embedded slides from Massachusetts General Hospital and Dana-Farber Cancer Institute. We would like to thank Dr. Hannes Vogel for reviewing the immunohistochemistry slides.

Conflict of interest

The authors declare that they have no conflict of interest with the sponsor of this research.

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Authors and Affiliations

  1. Department of Neurosurgery, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305, USA

    Gordon Li, Siddhartha S. Mitra, Kristy N. Henrich, Ryan T. Nitta & Albert J. Wong

  2. Department of Neurology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305, USA

    Michelle Monje

  3. Department of Pathology, Cytogenetics Laboratory, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305, USA

    C. Dana Bangs

  4. Institute of Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Research and Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA, 94305, USA

    Siddhartha S. Mitra

  5. Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Rd, MSLS, P309, Stanford, CA, 94305, USA

    Gordon Li

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  1. Gordon Li
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  2. Siddhartha S. Mitra
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  3. Michelle Monje
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  7. Albert J. Wong
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Corresponding authors

Correspondence to Gordon Li or Albert J. Wong.

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11060_2012_842_MOESM1_ESM.docx

Supplemental Figure 1: Maintenance of EGFRvIII in DIPG-1 tumorsphere line was observed at passage 21. Co-stain with anti-nestin antibody shows >80% of the cells to co-express EGFRvIII and nestin (DOCX 43.3 kb)

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Li, G., Mitra, S.S., Monje, M. et al. Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas. J Neurooncol 108, 395–402 (2012). https://doi.org/10.1007/s11060-012-0842-3

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  • DOI: https://doi.org/10.1007/s11060-012-0842-3

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