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EGFRvIII as a promising target for antibody-based brain tumor therapy

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Abstract

Cell surface receptors are attractive candidates for targeted therapy of cancer. Growth factors and their receptors play important roles in the regulation of cell division, development, and differentiation. Among those, the epidermal growth factor receptor (EGFR) was the first identified to be amplified and/or rearranged in malignant gliomas. The most common rearranged form, EGFR type III variant (EGFRvIII), has a deletion in its extracellular domain that results in the formation of a new, tumor-specific target found in glioblastoma multiforme, as well as in breast, ovarian, prostate, and lung carcinomas. Monoclonal antibodies have been developed with specific activity against this mutant receptor. These antibodies are internalized into the cell after receptor binding. Specific antibodies, either unarmed or armed with cytotoxic agents, including radioisotopes and toxins, have shown a promising role for EGFRvIII as a target for brain tumor therapy.

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References

  1. Davis FG, Preston-Martin S (1998) Epideniology: incidence and survival. In: Bigner DD, McClendon RE, Bruner JM (eds) Russell and Rubinstein's pathology of tumors of the nervous system. Arnold, London, pp 5–46

    Google Scholar 

  2. Grovas A, Gremgen A, Rauck A, et al. (1997) The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer 80:2321–2332

    Article  PubMed  CAS  Google Scholar 

  3. Walker MD, Alexander E, Hunt WE, et al. (1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333–343

    Article  PubMed  CAS  Google Scholar 

  4. Cokgor I, Akabani G, Kuan CT, et al. (2000) Phase I trial results of131I-labeled anti-tenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas. J Clin Oncol 18:3862–3872

    PubMed  CAS  Google Scholar 

  5. Libermann TA, Nusbaum HR, Razon N, et al. (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313:144–147

    Article  PubMed  CAS  Google Scholar 

  6. Wong AJ, Ruppert JM, Bigner SH, et al. (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969

    Article  PubMed  CAS  Google Scholar 

  7. Frederick L, Wang XY, Eley G, et al. (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387

    PubMed  CAS  Google Scholar 

  8. Wikstrand CJ, Reist CJ, Archer GF, et al. (1998) The class III variant of the epidermal growth factor receptor [EGFRvIII]: characterization and utilization as an immunotherapeutic target. J Neuro Virol 4:148–158

    CAS  Google Scholar 

  9. Nagane M, Huang HJS, Cavenee WK (1997) Advances in the molecular genetics of gliomas. Curr Opin Oncol 9:215–222

    PubMed  CAS  Google Scholar 

  10. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-Oncology 1:44–51

    Article  PubMed  CAS  Google Scholar 

  11. Di Fiore PP, Pierce JH, Fleming TP, et al. (1987) Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell 51:1063–1070

    Article  PubMed  Google Scholar 

  12. Velu TJ, Beguinot L, Vass WC, et al. (1987) Epidermal-growth-factor-dependent transformation by a human EGF receptor protooncogene. Science 238:1408–1410

    PubMed  CAS  Google Scholar 

  13. Neal DE, Sharples L, Smith K, et al. (1990) The epidermal growth factor receptor and the prognosis of bladder cancer. Cancer 65:1619–1625

    Article  PubMed  CAS  Google Scholar 

  14. Libermann TA, Razon N, Bartal AD, et al. (1984) Expression of epidermal growth factor receptors in human brain tumors. Cancer Res 44:753–760

    PubMed  CAS  Google Scholar 

  15. Watanabe K, Tachibana O, Sata K, et al. (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–224

    PubMed  CAS  Google Scholar 

  16. Carpenter G, Cohen S (1990) Epidermal growth factor. J Biol Chem 265:7709–7712

    PubMed  CAS  Google Scholar 

  17. Agosti RM, Leuthold M, Gullick WJ, et al. (1992) Expression of the epidermal growth factor receptor in astrocytic tumours is specifically associated with glioblastoma multiforme. Virchows Archiv A, Pathol Anat Histopathol 420:321–325

    Article  CAS  Google Scholar 

  18. Ekstrand AJ, Sugawa N, James CD, et al. (1992) Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad Sci USA 89: 4309–4313

    Article  PubMed  CAS  Google Scholar 

  19. Schlegel J, Merdes A, Stumm G, et al. (1994) Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma. Int J Cancer 56:72–77

    Article  PubMed  CAS  Google Scholar 

  20. Chaffanet M, Chauvin C, Laine M, et al. (1992) EGF receptor amplification and expression in human brain tumours. Eur J Cancer 28:11–17

    Article  PubMed  CAS  Google Scholar 

  21. Tsugu A, Kijima H, Yamazaki H, et al. (1997) Localization of aberrant messenger RNA of epidermal growth factor receptor (EGFR) in malignant glioma. Anticancer Res 17:2225–2232

    PubMed  CAS  Google Scholar 

  22. Waksal HW (1999) Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev 18:427–436

    Article  PubMed  CAS  Google Scholar 

  23. Yang X-D, Jia X-C, Corvalan JRF, et al. (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 59:1236–1243

    PubMed  CAS  Google Scholar 

  24. Bigner SH, Batra SK, Rasheed BKA (1998) Mechanisms of altered growth control. Cytogenetics, oncogenes and suppressor genes. In: Bigner DD, McLendon RE, Bruner JM (eds) Russell and Rubinstein's pathology of the nervous system. Arnold, London, pp 47–82

    Google Scholar 

  25. Bigner SH, Humphrey PA, Wong AJ, et al. (1990) Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 50:8017–8022

    PubMed  CAS  Google Scholar 

  26. Ekstrand AJ, James CD, Cavenee WK, et al. (1991) Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51:2164–2172

    PubMed  CAS  Google Scholar 

  27. Humphrey PA, Wong AJ, Vogelstein B, et al. (1990) Antisynthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87:4207–4211

    Article  PubMed  CAS  Google Scholar 

  28. Yamazaki H, Ohba Y, Tamaoki N, et al. (1990) A deletion mutation within the ligand binding domain is responsible for activation of epidermal growth factor receptor gene in human brain tumors. Jpn J Cancer Res 81:773–779

    PubMed  CAS  Google Scholar 

  29. Garcia de Palazzo IE, Adams GP, Sundareshan P, et al. (1993) Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. Cancer Res 53:3217–3220

    PubMed  CAS  Google Scholar 

  30. Moscatello DC, Holgado-Madruga M, Godwin AK, et al. (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55:5536–5539

    PubMed  CAS  Google Scholar 

  31. Wikstrand CJ, Hale LP, Batra SK, et al. (1995) Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 55:3140–3148

    PubMed  CAS  Google Scholar 

  32. Wikstrand CJ, McLendon RE, Friedman AH, et al. (1997) Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res 57:4130–4140

    PubMed  CAS  Google Scholar 

  33. Wikstrand CJ, Fung KM, Trojanowski JQ, et al. (1998) Antibodies and molecular immunology: immunohistochemistry and antigens of diagnostic significance. In: Bigner DD, McLendon RE, Bruner JM (eds) Russell and Rubinstein's pathology of the nervous system. Arnold, London, pp 251–304

    Google Scholar 

  34. Nishikawa R, Ji SC, Harmon RC, et al. (1994) A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 91:7727–7731

    Article  PubMed  CAS  Google Scholar 

  35. Batra SK, Castelino-Prabhu S, Wikstrand CJ, et al. (1995) Epidermal growth factor ligand-independent, unregulated, celltransforming potential of a naturally occurring human mutantEGFRvIII gene. Cell Growth Differ 6:1251–1259

    PubMed  CAS  Google Scholar 

  36. Huang HS, Nagane M, Klingbeil CK, et al. (1997) The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 272:2927–2935

    Article  PubMed  CAS  Google Scholar 

  37. Nagane M, Coufal F, Lin H, et al. (1996) A common mutant epidermal growth factor receptor enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res 56:5079–5086

    PubMed  CAS  Google Scholar 

  38. Chu CT, Everiss KD, Wikstrand CJ, et al. (1997) Receptor dimerization is not a factor in the signaling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 324:855–861

    PubMed  CAS  Google Scholar 

  39. Moscatello DK, Montgomery RV, Sundaresham P, et al. (1996) Transformation and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene 13:85–96

    PubMed  CAS  Google Scholar 

  40. Prigent SA, Nagane M, Lin H, et al. (1996) Enhanced tumorigenic behavior of glioblastoma cells expressing a truncated epidermal growth factor receptor is mediated through the Ras-Shc-Grb2 pathway. J Biol Chem 271:25639–25645

    Article  PubMed  CAS  Google Scholar 

  41. Moscatello DK, Holgado-Madruga M, Emlet DR, et al. (1998) Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem 273:200–206

    Article  PubMed  CAS  Google Scholar 

  42. Antonyak MA, Moscatello DK, Wong AJ (1998) Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem 273:2817–2822

    Article  PubMed  CAS  Google Scholar 

  43. Nagane M, Levitzki A, Gazit A, et al. (1998) Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and capase-3-like proteases. Proc Natl Acad Sci USA 95:5724–5729

    Article  PubMed  CAS  Google Scholar 

  44. Montgomery RB, Guzman J, O'Rourke DM, et al. (2000) Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 275:17358–17363

    Article  PubMed  CAS  Google Scholar 

  45. Tang CK, Gong XQ, Moscatello DK, et al. (2000) Epidermal growth factor receptor vIII enhances tumorigenicity in human breast cancer. Cancer Res 60:3081–3087

    PubMed  CAS  Google Scholar 

  46. Reist CJ, Archer GE, Kurpad SN, et al. (1995) Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts. Cancer Res 55:4375–4382

    PubMed  CAS  Google Scholar 

  47. Kuan CT, Reist CJ, Foulon CF, et al. (1999)125I-labeled anti-epidermal growth factor receptor-vIII single chain Fv exhibits specific and high-level targeting of glioma xenografts. Clin Cancer Res 5:1539–1549

    PubMed  CAS  Google Scholar 

  48. Kuan CT, Wikstrand CJ, Archer GE, et al. (2000) Increased binding affinity enhances targeting of glioma xenografts by EGFRvIII-specific scFv. Int J Cancer (in press)

  49. Reist CJ, Batra SW, Pegram CN, et al. (1997) In vitro and in vivo behavior of radiolabeled chimeric anti-EGFRvIII monoclonal antibody: comparison with its murine parent. Nucl Med Biol 24:637–647

    Article  Google Scholar 

  50. Lorimer IAJ, Deppler-Hafkemeyer A, Beers RA, et al. (1996) Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display. Proc Natl Acad Sci USA 93:14815–14820

    Article  PubMed  CAS  Google Scholar 

  51. Beers R, Chowdhury P, Bigner D et al. (2000) Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display. Clin Cancer Res 6:2835–2843

    PubMed  CAS  Google Scholar 

  52. Goldstein JI, Prewett M, Zuklys L, et al. (1995) Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1:1311–1318

    PubMed  CAS  Google Scholar 

  53. Sampson JH, Crotty LE, Lee S, et a. (2000) Unarmed, tumor-specific, monoclonal antibody effectively treats brain tumors through antibody-dependent cell-mediated cytotoxicity. Proc Natl Acad Sci USA 97:7503–7508

    Article  PubMed  CAS  Google Scholar 

  54. Wikstrand CJ, Cokgor I, Sampson JH, et al. (1999) Monoclonal antibody therapy of human gliomas: current status and future approaches. Cancer Metastasis Rev 18:451–464

    Article  PubMed  CAS  Google Scholar 

  55. Reist CJ, Archer GE, Wikstrand CJ, et al. (1997) Improved targeting of an anti-EGFRvIII monoclonal antibody in tumor xenografts after labeling using N-succinimidyl 5-iodo-3-pyridinecarboxylate. Cancer Res 57:1510–1515

    PubMed  CAS  Google Scholar 

  56. Schmidt M, Reiser P, Hills D, et al. (1998) Expression of an oncogenic mutant EGF receptor markedly increases the sensitivity of cells to an EGF-receptor-specific antibody-toxin. Int J Cancer 75:878–884

    Article  PubMed  CAS  Google Scholar 

  57. Schmidt M, Maurer-Gebhard M, Groner B, et al. (1999) Suppression of metastasis formation by a recombinant single chain antibody-toxin targeted to full length and oncogenic variant EGF receptors. Oncogene 18:1711–1721

    Article  PubMed  CAS  Google Scholar 

  58. Lorimer IA, Wikstrand CJ, Batra SK, et al. (1995) Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res 1:859–864

    PubMed  CAS  Google Scholar 

  59. Archer GE, Simpson JH, Lorimer IAJ, et al. (1999) Regional treatment of EGFRvIII-expressing neoplastic meningitis with a single chain immunotoxin MR1. Clin Cancer Res 5:2646–2652

    PubMed  CAS  Google Scholar 

  60. Wikstrand CJ, Sampson JH, Bigner DD (2000) EGFRvIII: an oncogene deletion mutant cell surface receptor target expressed by multiple tumor types. Emerging Ther Targets 4:497–514

    Article  CAS  Google Scholar 

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  1. Department of Pathology, Duke University Medical Center, 177 Medical Sciences Research Building, Box 3156, 27710, Durham, NC, USA

    Chien-Tsun Kuan, Carol J. Wikstrand & Darell D. Bigner

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  1. Chien-Tsun Kuan
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  2. Carol J. Wikstrand
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  3. Darell D. Bigner
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Correspondence to Darell D. Bigner.

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Kuan, CT., Wikstrand, C.J. & Bigner, D.D. EGFRvIII as a promising target for antibody-based brain tumor therapy. Brain Tumor Pathol 17, 71–78 (2000). https://doi.org/10.1007/BF02482738

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