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. 2006 Apr 5;13(1):52–61. doi: 10.1111/j.1750-3639.2003.tb00006.x

Targeted Molecular Therapy of GBM

Paul S Mischel 1,3,✉, Timothy F Cloughesy 2,3
PMCID: PMC8095874  PMID: 12580545

Abstract

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the PI3K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand‐independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.

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References

  • 1. Adjei AA, Davis JN, Bruzek LM, Erlichman C, Kaufmann SH (2001) Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin Cancer Res 7:1438–1445. [PubMed] [Google Scholar]
  • 2. Ansher SS, Scharf R (2001) The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute: industry collaborations in new agent development. Ann N YAcad Sci 949:333–340. [DOI] [PubMed] [Google Scholar]
  • 3. Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, et al (2001) Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase‐2. Cancer Res 61:8730–8736. [PubMed] [Google Scholar]
  • 4. Boehm T, Folkman J, Browder T, O'Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390:404–407. [DOI] [PubMed] [Google Scholar]
  • 5. Brady LW, Miyamoto C, Woo DV, Rackover M, Emrich J, Bender H, Dadparvar S, Steplewski Z, Koprowski H, Black P, et al (1992) Malignant astrocytomas treated with iodine‐125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial. Int J Radiat Oncol Biol Phys 22:225–230. [DOI] [PubMed] [Google Scholar]
  • 6. Brat DJ, Van Meir EG (2001) Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am J Pathol 158:789–796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Carter P (2001) Improving the efficacy of antibody‐based cancer therapies. Nat Rev Cancer 1:118–129. [DOI] [PubMed] [Google Scholar]
  • 8. Chavakis E, Dimmeler S (2002) Regulation of endothelial cell survival and apoptosis during angiogenesis. Arterioscler Thromb Vasc Biol 22:887–893. [DOI] [PubMed] [Google Scholar]
  • 9. Cheng Y, Ng HK, Ding M, Zhang SF, Pang JC, Lo KW (1999) Molecular analysis of microdissected de novo glioblastomas and paired astrocytic tumors. J Neuropathol Exp Neurol 58:120–128. [DOI] [PubMed] [Google Scholar]
  • 10. Choe G, Park JK, Joubin‐Steele L, Kremen TJ, Liau LM, Vinters HV, Cloughesy TF, Mischel PS (2002) Active MMP‐9 expression is associated with primary glioblastoma subtype. Clinical Cancer Research 8:2894–2901. [PubMed] [Google Scholar]
  • 11. Cloughesy TF, Kuhn J, Wen P, Chang SM, Schiff D, Greenberg H, Junck L, Robins I, DeAngelis L, Yung A, Groves et al (2002) Phase II trial of R11577 (Zarnestra) in patients with recurrent glioma not taking enzyme inducing antiepileptic drugs (EIAED): a North American Brain Tumor Consortium (NABTC) report. Proc Am Soc Clin Oncol .
  • 12. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G et al (1999) Multinational study of the efficacy and safety of humanized anti‐HER2 monoclonal antibody in women who have HER2‐overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648. [DOI] [PubMed] [Google Scholar]
  • 13. Coffey MC, Strong JE, Forsyth PA, Lee PW (1998) Reovirus therapy of tumors with activated Ras pathway. Science 282:1332–1334. [DOI] [PubMed] [Google Scholar]
  • 14. Drevs J, Muller‐Driver R, Wittig C, Fuxius S, Esser N, Hugenschmidt H, Konerding MA, Allegrini PR, Wood J, Hennig J et al (2002) PTK787/ZK 222584, a specific vascular endothelial growth factor‐receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res 62:4015–4022. [PubMed] [Google Scholar]
  • 15. Druker BJ (2002) Perspectives on the development of a molecularly targeted agent. Cancer Cell 1:31–36. [DOI] [PubMed] [Google Scholar]
  • 16. Ekstrand AJ, Sugawa N, James CD, Collins VP (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 U S A 89:4309–4313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Feldkamp MM, Lala P, Lau N, Roncari L, Guha A (1999) Expression of activated epidermal growth factor receptors, Ras‐ guanosine triphosphate, and mitogen‐activated protein kinase in human glioblastoma multiforme specimens. Neurosurgery 45:1442–1453. [DOI] [PubMed] [Google Scholar]
  • 18. Feldkamp MM, Lau N, Guha A (1999) The farnesyltrans‐ferase inhibitor L‐744,832 inhibits the growth of astrocytomas through a combination of antiproliferative, antiangiogenic, and proapoptotic activities. Ann N Y Acad Sci 886:257–260. [DOI] [PubMed] [Google Scholar]
  • 19. Fernandez N, Duffour MT, Perricaudet M, Lotze MT, Tursz T, Zitvogel L (1998) Active specific T‐cell‐based immunotherapy for cancer: nucleic acids, peptides, whole native proteins, recombinant viruses, with dendritic cell adjuvants or whole tumor cell‐based vaccines. Principles and future prospects. Cytokines Cell Mol Ther 4:53–65. [PubMed] [Google Scholar]
  • 20. Folkman J (1999) Angiogenesis research: from laboratory to clinic. Forum (Genova) 9:59–62. [PubMed] [Google Scholar]
  • 21. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, et al (1999) SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk‐1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59:99–106. [PubMed] [Google Scholar]
  • 22. Foulon CF, Reist CJ, Bigner DD, Zalutsky MR (2000) Radioiodination via D‐amino acid peptide enhances cellular retention and tumor xenograft targeting of an internalizing anti‐epidermal growth factor receptor variant III monoclonal antibody. Cancer Res 60:4453–4460. [PubMed] [Google Scholar]
  • 23. Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387. [PubMed] [Google Scholar]
  • 24. Geng L, Donnelly E, McMahon G, Lin PC, Sierra‐Rivera E, Oshinka H, Hallahan DE (2001) Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 61:2413–2419. [PubMed] [Google Scholar]
  • 25. Geoerger B, Grill J, Opolon P, Morizet J, Aubert G, Terrier‐Lacombe MJ, Bressac De‐Paillerets B, Barrois M, Feunteun J, Kirn DH et al (2002) Oncolytic activity of the E1B–55 kDa‐deleted adenovirus ONYX–015 is independent of cellular p53 status in human malignant glioma xenografts. Cancer Res 62:764–772. [PubMed] [Google Scholar]
  • 26. Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′‐kinase/Akt signal transduction pathway. Requirement for Flk‐1/KDR activation. J Biol Chem 273:30336–30343. [DOI] [PubMed] [Google Scholar]
  • 27. Glass TL, Liu TJ, Yung WK (2000) Inhibition of cell growth in human glioblastoma cell lines by farnesyltransferase inhibitor SCH66336. Neuro-oncol 2:151–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Gurney JG, Kadan‐Lottick N (2001) Brain and other central nervous system tumors: rates, trends, and epidemiology. Curr Opin Oncol 13:160–166. [DOI] [PubMed] [Google Scholar]
  • 29. Hall AR, Dix BR, O'Carroll SJ, Braithwaite AW (1998) p53‐dependent cell death/apoptosis is required for a productive adenovirus infection. Nat Med 4:1068–1072. [DOI] [PubMed] [Google Scholar]
  • 30. Hayashi Y, Ueki K, Waha A, Wiestler OD, Louis DN, von Deimling A (1997) Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. Brain Pathol 7:871–875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Hills D, Rowlinson‐Busza G, Gullick WJ (1995) Specific targeting of a mutant, activated FGF receptor found in glioblastoma using a monoclonal antibody. Int J Cancer 63:537–543. [DOI] [PubMed] [Google Scholar]
  • 32. Hunt S (2001) Technology evaluation: IMC‐1C11, ImClone Systems. Curr Opin Mol Ther 3:418–424. [PubMed] [Google Scholar]
  • 33. Iruela‐Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD (1999) Inhibition of angiogenesis by thrombospondin‐1 is mediated by 2 independent regions within the type 1 repeats. Circulation 100:1423–1431. [DOI] [PubMed] [Google Scholar]
  • 34. Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM, Cheng JQ (2000) The phosphoinositide 3‐OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor‐induced apoptosis. Mol Cell Biol 20:139–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Joki T, Machluf M, Atala A, Zhu J, Seyfried NT, Dunn IF, Abe T, Carroll RS, Black PM (2001) Continuous release of endostatin from microencapsulated engineered cells for tumor therapy. Nat Biotechnol 19:35–39. [DOI] [PubMed] [Google Scholar]
  • 36. Jung V, Romeike BF, Henn W, Feiden W, Moringlane JR, Zang KD, Urbschat S (1999) Evidence of focal genetic microheterogeneity in glioblastoma multiforme by area‐specific CGH on microdissected tumor cells. J Neuropathol Exp Neurol 58:993–999. [DOI] [PubMed] [Google Scholar]
  • 37. Karp JE, Kaufmann SH, Adjei AA, Lancet JE, Wright JJ, End DW (2001) Current status of clinical trials of farnesyltransferase inhibitors. Curr Opin Oncol 13:470–476. [DOI] [PubMed] [Google Scholar]
  • 38. Kilic T, Alberta JA, Zdunek PR, Acar M, Iannarelli P, O'Reilly T, Buchdunger E, Black PM, Stiles CD (2000) Intracranial inhibition of platelet‐derived growth factormediated glioblastoma cell growth by an orally active kinase inhibitor of the 2‐ phenylaminopyrimidine class. Cancer Res 60:5143–5150. [PubMed] [Google Scholar]
  • 39. Kirn D (2000) Replication‐selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 19:6660–6669. [DOI] [PubMed] [Google Scholar]
  • 40. Kirn D (2001) Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx‐015): results of phase I and II trials. Expert Opin Biol Ther 1:525–538. [DOI] [PubMed] [Google Scholar]
  • 41. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225; discussion 226–219. [DOI] [PubMed] [Google Scholar]
  • 42. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1:44–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Kuan CT, Wikstrand CJ, Bigner DD (2001) EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 8:83–96. [DOI] [PubMed] [Google Scholar]
  • 44. Lawler J (2002) Thrombospondin‐1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med 6:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Levin VA (1999) Chemotherapy for brain tumors of astrocytic and oligodendroglial lineage: the past decade and where we are heading. Neuro-oncol 1:69–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Liau LM, Lallone RL, Seitz RS, Buznikov A, Gregg JP, Kornblum HI, Nelson SF, Bronstein JM (2000) Identification of a human glioma‐associated growth factor gene, granulin, using differential immuno‐absorption. Cancer Res 60:1353–1360. [PubMed] [Google Scholar]
  • 47. Liu W, James CD, Frederick L, Alderete BE, Jenkins RB (1997) PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. Cancer Res 57:5254–5257. [PubMed] [Google Scholar]
  • 48. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA (2002) Platelet‐derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF‐C and PDGF‐D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735. [PubMed] [Google Scholar]
  • 49. Lorimer IA, Keppler‐Hafkemeyer A, Beers RA, Pegram CN, Bigner DD, Pastan I (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 U S A 93:14815–14820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Markert JM, Gillespie GY, Weichselbaum RR, Roizman B, Whitley RJ (2000) Genetically engineered HSV in the treatment of glioma: a review. Rev Med Virol 10:17–30. [DOI] [PubMed] [Google Scholar]
  • 51. McLaughlin P, Hagemeister FB, Grillo‐Lopez AJ (1999) Rit‐uximab in indolent lymphoma: the single‐agent pivotal trial. Semin Oncol 26:79–87. [PubMed] [Google Scholar]
  • 52. Mishima K, Johns TG, Luwor RB, Scott AM, Stockert E, Jungbluth AA, Ji XD, Suvarna P, Voland JR, Old LJ, et al (2001) Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 61:5349–5354. [PubMed] [Google Scholar]
  • 53. Nagane M, Lin H, Cavenee WK, Huang HJ (2001) Aberrant receptor signaling in human malignant gliomas: mechanisms and therapeutic implications. Cancer Lett 162 Suppl:S17–S21. [DOI] [PubMed] [Google Scholar]
  • 54. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18:1135–1149. [DOI] [PubMed] [Google Scholar]
  • 55. Nelson NJ (1999) Angiogenesis research is on fast forward. J Natl Cancer Inst 91:820–822. [DOI] [PubMed] [Google Scholar]
  • 56. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL (2001) Enhanced sensitivity of PTEN‐deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ (1994) A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 91:7727–7731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Nozaki M, Tada M, Kobayashi H, Zhang CL, Sawamura Y, Abe H, Ishii N, Van Meir EG (1999) Roles of the functional loss of p53 and other genes in astrocytoma tumorigenesis and progression. Neuro-oncol 1:124–137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Oehler MK, Bicknell R (2000) The promise of anti‐angiogenic cancer therapy. Br J Cancer 82:749–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. O'Reilly MS, Holmgren L, Chen C, Folkman J (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2:689–692. [DOI] [PubMed] [Google Scholar]
  • 61. Park JW (2002) Liposome‐based drug delivery in breast cancer treatment. Breast Cancer Res 4:95–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Rosen LS (2002) Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 9:36–44. [DOI] [PubMed] [Google Scholar]
  • 63. Sampson JH, Crotty LE, Lee S, Archer GE, Ashley DM, Wikstrand CJ, Hale LP, Small C, Dranoff G, Friedman AH et al (2000) Unarmed, tumor‐specific monoclonal antibody effectively treats brain tumors. Proc Natl Acad Sci U S A 97:7503–7508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Schmidt EE, Ichimura K, Goike HM, Moshref A, Liu L, Collins VP (1999) Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. J Neuropathol Exp Neurol 58:1170–1183. [DOI] [PubMed] [Google Scholar]
  • 65. Shawver LK, Slamon D, Ullrich A (2002) Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1:117–123. [DOI] [PubMed] [Google Scholar]
  • 66. Siwak DR, Tari AM, Lopez‐Berestein G (2002) The potential of drug‐carrying immunoliposomes as anticancer agents Commentary re: J. W. Park et al. Anti‐HER2 immunoliposomes: enhanced efficacy due to targeted delivery. Clin. Cancer Res, 8: 1172–1181, 2002. Clin Cancer Res 8:955–956. [PubMed] [Google Scholar]
  • 67. Slamon D, Pegram M (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28:13–19. [DOI] [PubMed] [Google Scholar]
  • 68. Slamon DJ, Leyland‐Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. [DOI] [PubMed] [Google Scholar]
  • 69. Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O'Fallon JR, Schaefer PL, Scheithauer BW, James CD, et al (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256. [DOI] [PubMed] [Google Scholar]
  • 70. Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, Dvorak AM, Dvorak HF (2001) Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor‐164 gene delivery. Am J Pathol 158:1145–1160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Tenan M, Fulci G, Albertoni M, Diserens AC, Hamou MF, El Atifi‐Borel M, Feige JJ, Pepper MS, Van Meir EG (2000) Thrombospondin‐1 is downregulated by anoxia and suppresses tumorigenicity of human glioblastoma cells. J Exp Med 191:1789–1798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H (1998) PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 57:684–689. [DOI] [PubMed] [Google Scholar]
  • 73. Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, O'Reilly T, Wood J, Zimmermann J (2001) Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Rev 21:499–512. [DOI] [PubMed] [Google Scholar]
  • 74. Vajkoczy P, Menger MD, Vollmar B, Schilling L, Schmiedek P, Hirth KP, Ullrich A, Fong TA (1999) Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk‐1 inhibitor SU5416 as assessed by intravital multi‐ fluorescence videomicroscopy. Neoplasia 1:31–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3‐Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501. [DOI] [PubMed] [Google Scholar]
  • 76. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, et al (2002) Efficacy and safety of trastuzumab as a single agent in first‐line treatment of HER2‐overexpressing metastatic breast cancer. J Clin Oncol 20:719–726. [DOI] [PubMed] [Google Scholar]
  • 77. von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN (1993) Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26. [DOI] [PubMed] [Google Scholar]
  • 78. Wang QC, Pai LH, Debinski W, FitzGerald DJ, Pastan I (1993) Polyethylene glycol‐modified chimeric toxin composed of transforming growth factor alpha and Pseudomonas exotoxin. Cancer Res 53:4588–4594. [PubMed] [Google Scholar]
  • 79. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–223; discussion 223–214. [DOI] [PubMed] [Google Scholar]
  • 80. Wen PY, Yung WK, Hess K, Silberman S, Hayes M, Schiff D, Lieberman F, Cloughesy TF, DeAngeles LM, Chang SM et al (2002) Phase I study of STI571 (Gleevec) for patients with recurrent malignant gliomas and meningiomas (NABTC 99–08). Proc Am Soc Clin Oncol :
  • 81. Wikstrand CJ, Cokgor I, Sampson JH, Bigner DD (1999) Monoclonal antibody therapy of human gliomas: current status and future approaches. Cancer Metastasis Rev 18:451–464. [DOI] [PubMed] [Google Scholar]
  • 82. Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, McLendon RE, Moscatello D, Pegram CN, Reist CJ, 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] [Google Scholar]
  • 83. Wikstrand CJ, McLendon RE, Friedman AH, Bigner DD (1997) Cell surface localization and density of the tumorassociated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res 57:4130–4140. [PubMed] [Google Scholar]
  • 84. Wikstrand CJ, Reist CJ, Archer GE, Zalutsky MR, Bigner DD (1998) The class III variant of the epidermal growth factor receptor (EGFRvIII): characterization and utilization as an immunotherapeutic target. J Neurovirol 4:148–158. [DOI] [PubMed] [Google Scholar]
  • 85. Wilcox ME, Yang W, Senger D, Rewcastle NB, Morris DG, Brasher PM, Shi ZQ, Johnston RN, Nishikawa S, Lee PW, et al (2001) Reovirus as an oncolytic agent against experimental human malignant gliomas. J Natl Cancer Inst 93:903–912. [DOI] [PubMed] [Google Scholar]
  • 86. Yung WK, Friedman H, Jackson E, Provenzale J, Leeds N, Conrad C, Walker A, Henry A, Huang J, Laurent D, Dugan M (2002) A phase I trial of PTK787/Zk 22584 (PTK/ZK), a novel oral VEGFR TK inhibitor in recurrent glioblastoma. Proc Am Soc Clin Oncol .
  • 87. Zagzag D, Capo V (2002) Angiogenesis in the central nervous system: a role for vascular endothelial growth factor/vascular permeability factor and tenascin‐C. Common molecular effectors in cerebral neoplastic and non‐neoplastic “angiogenic diseases. Histol Histopathol 17:301–321. [DOI] [PubMed] [Google Scholar]
  • 88. Zhang Y, Zhu C, Pardridge WM (2002) Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Mol Ther 6:67–72. [DOI] [PubMed] [Google Scholar]

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