, Volume 6, Issue 3, pp 500–512 | Cite as

Targeted therapy for malignant glioma patients: Lessons learned and the road ahead

  • Tiffany T. Huang
  • Shawn M. Sarkaria
  • Timothy F. Cloughesy
  • Paul S. Mischel
Review Article


Molecularly targeted therapies are transforming the care of patients with malignant gliomas, including glioblastoma, the most common malignant primary brain tumor of adults. With an arsenal of small molecule inhibitors and antibodies that target key components of the signal transduction machinery that are commonly activated in gliomas, neurooncologists and neurosurgeons are poised to transform the care of these patients. Nonetheless, successful application of targeted therapies remains a challenge. Strategies are lacking for directing kinase inhibitor or other pathway-specific therapies to individual patients most likely to benefit. In addition, response to targeted agents is determined not only by the presence of the key mutant kinases, but also by other critical changes in the molecular circuitry of cancer cells, such as loss of key tumor suppressor proteins, the selection for kinase-resistant mutants, and the deregulation of feedback loops. Understanding these signaling networks, and studying them in patients, will be critical for developing rational combination therapies to suppress resistance for malignant glioma patients. Here we review the current status of molecular targeted therapies for malignant gliomas. We focus initially on identifying some of the insights gained to date from targeting the EGFR/PI3K/Akt/mTOR signaling pathway in patients and on how this has led toward a reconceptualization of some of the challenges and directions for targeted treatment. We describe how advances from the world of genomics have the potential to transform our approaches toward targeted therapy, and describe how a deeper understanding of the complex nature of cancer, and its adeptness at rewiring molecular circuitry to evade targeted agents, has raised new challenges and identified new leads.

Key Words

Glioma growth factors molecular targeted therapy microenvironment coactivation 


  1. 1.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100: 57–70.PubMedGoogle Scholar
  2. 2.
    Bishop JM. Molecular themes in oncogenesis. Cell 1991;64: 235–248.PubMedGoogle Scholar
  3. 3.
    Bruna A, Darken RS, Rojo F, et al. High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 2007;11: 147–160.PubMedGoogle Scholar
  4. 4.
    Yoshida D, Kim K, Noha M, Teramoto A. Hypoxia inducible factor 1-alpha regulates of platelet derived growth factor-B in human glioblastoma cells. J Neurooncol 2006;76: 13–21.PubMedGoogle Scholar
  5. 5.
    Arrieta O, Garcia E, Guevara P, et al. Hepatocyte growth factor is associated with poor prognosis of malignant gliomas and is a predictor for recurrence of meningioma. Cancer 2002;94: 3210–3218.PubMedGoogle Scholar
  6. 6.
    Koochekpour S, Jeffers M, Rulong S, et al. Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res 1997;57: 5391–5398.PubMedGoogle Scholar
  7. 7.
    Uchinokura S, Miyata S, Fukushima T, et al. Role of hepatocyte growth factor activator (HGF activator) in invasive growth of human glioblastoma cells in vivo. Int J Cancer 2006;118: 583–592.PubMedGoogle Scholar
  8. 8.
    Reznik TE, Sang Y, Ma Y, et al. Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res 2008;6: 139–150.PubMedGoogle Scholar
  9. 9.
    Huang H, Held-Feindt J, Buhl R, Mehdorn HM, Mentlein R. Expression of VEGF and its receptors in different brain tumors. Neurol Res 2005;27: 371–377.PubMedGoogle Scholar
  10. 10.
    Ningaraj NS, Rao MK, Black KL. Adenosine 5′-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model. Cancer Res 2003;63: 8899–8911.PubMedGoogle Scholar
  11. 11.
    Cerletti A, Drewe J, Flicker G, Eberle AN, Huwyler J. Endocytosis and transcytosis of an immunoliposome-based brain drug delivery system. J Drug Target 2000;8: 435–446.PubMedGoogle Scholar
  12. 12.
    Deguchi Y, Kurihara A, Pardridge WM. Retention of biologic activity of human epidermal growth factor following conjugation to a blood-brain barrier drug delivery vector via an extended poly(ethylene glycol) linker. Bioconjug Chem 1999;10: 32–37.PubMedGoogle Scholar
  13. 13.
    Badruddoja MA, Black KL. Improving the delivery of therapeutic agents to CNS neoplasms: a clinical review. Front Biosci 2006;11: 1466–1478.PubMedGoogle Scholar
  14. 14.
    Fan QW, Cheng C, Knight ZA, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma [Erratum in: Sci Signal 2009;2(60):er4]. Sci Signal 2009;2(55): ra4.PubMedGoogle Scholar
  15. 15.
    Li L, Dutra A, Pak E, et al. EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. Neuro Oncol 2009;11: 9–21.PubMedGoogle Scholar
  16. 16.
    Pore N, Liu S, Haas-Kogan DA, O’Rourke DM, Maity A. PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res 2003;63: 236–241.PubMedGoogle Scholar
  17. 17.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455: 1061–1068.Google Scholar
  18. 18.
    Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321: 1807–1812.PubMedGoogle Scholar
  19. 19.
    Bachoo RM, Maher EA, Ligon KL, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 2002;1: 269–277.PubMedGoogle Scholar
  20. 20.
    Holland EC. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2001;2: 120–129.PubMedGoogle Scholar
  21. 21.
    Shannon P, Sabha N, Lau N, et al. Pathological and molecular progression of astrocytomas in a GFAP:12 V-Ha-Ras mouse astrocytoma model. Am J Pathol 2005;167: 859–867.PubMedGoogle Scholar
  22. 22.
    Wei Q, Clarke L, Scheidenhelm DK, et al. High-grade glioma formation results from postnatal Pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Res 2006;66: 7429–7437.PubMedGoogle Scholar
  23. 23.
    Weiss WA, Bums MJ, Hackett C, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res 2003;63: 1589–1595.PubMedGoogle Scholar
  24. 24.
    Xiao A, Wu H, Pandolfi PP, Louis DN, Van Dyke T. Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 2002;1: 157–168.PubMedGoogle Scholar
  25. 25.
    Zheng H, Ying H, Yan H, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 2008;455: 1129–1133.PubMedGoogle Scholar
  26. 26.
    Zhu Y, Guignard F, Zhao D, et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 2005;8: 119–130.PubMedGoogle Scholar
  27. 27.
    Kwon CH, Zhao D, Chen J, et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 2008;68: 3286–3294.PubMedGoogle Scholar
  28. 28.
    Sarkaria JN, Yang L, Grogan PT, et al. Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol Cancer Ther 2007;6: 1167–1174.PubMedGoogle Scholar
  29. 29.
    Choe G, Horvath S, Cloughesy TF, et al. Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 2003;63: 2742–2746.PubMedGoogle Scholar
  30. 30.
    Ermoian RP, Furniss CS, Lamborn KR, et al. Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res 2002;8: 1100–1106.PubMedGoogle Scholar
  31. 31.
    Riemenschneider MJ, Betensky RA, Pasedag SM, Louis DN. AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. Cancer Res 2006;66: 5618–5623.PubMedGoogle Scholar
  32. 32.
    Huang HS, Nagane M, Klingbeil CK, et al. 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 1997;272: 2927–2935.PubMedGoogle Scholar
  33. 33.
    Maruno M, Kovach JS, Kelly PJ, Yanagihara T. Transforming growth factor-alpha, epidermal growth factor receptor, and proliferating potential in benign and malignant gliomas. J Neurosurg 1991;75: 97–102.PubMedGoogle Scholar
  34. 34.
    Montgomery RB, Moscatello DK, Wong AJ, Cooper JA, Stahl WL. Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. J Biol Chem 1995;270: 30562–30566.PubMedGoogle Scholar
  35. 35.
    Samuels V, Barrett JM, Bockman S, Pantazis CG, Allen MB Jr. Immunocytochemical study of transforming growth factor expression in benign and malignant gliomas. Am J Pathol 1989;134: 894–902.PubMedGoogle Scholar
  36. 36.
    Wikstrand CJ, McLendon RE, Friedman AH, Bigner DD. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res 1997;57: 4130–4140.PubMedGoogle Scholar
  37. 37.
    Yung WK, Zhang X, Steck PA, Hung MC. Differential amplification of the TGF-alpha gene in human gliomas. Cancer Commun 1990;2: 201–205.PubMedGoogle Scholar
  38. 38.
    Yoshimoto K, Dang J, Zhu S, et al. Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples. Clin Cancer Res 2008;14: 488–493.PubMedGoogle Scholar
  39. 39.
    Huang PH, Mukasa A, Bonavia R, et al. Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci USA 2007;104: 12867–12872.PubMedGoogle Scholar
  40. 40.
    Frederick L, Eley G, Wang XY, James CD. Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements. Neuro Oncol 2000;2: 159–163.PubMedGoogle Scholar
  41. 41.
    Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60: 1383–1387.PubMedGoogle Scholar
  42. 42.
    Lee JC, Vivanco I, Beroukhim R, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 2006;3: e485.PubMedGoogle Scholar
  43. 43.
    Akbasak A, Sunar-Akbasak B. Oncogenes: cause or consequence in the development of glial tumors. J Neurol Sci 1992;111: 119–133.PubMedGoogle Scholar
  44. 44.
    Mishima K, Johns TG, Luwor RB, et al. 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 2001;61: 5349–5354.PubMedGoogle Scholar
  45. 45.
    Yamoutpour F, Bodempudi V, Park SE, et al. Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity. Mol Cancer Ther 2008;7: 3586–3597.PubMedGoogle Scholar
  46. 46.
    Martens T, Laabs Y, Gunther HS, et al. Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. Clin Cancer Res 2008;14: 5447–5458.PubMedGoogle Scholar
  47. 47.
    Haas-Kogan DA, Prados MD, Tihan T, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97: 880–887.PubMedGoogle Scholar
  48. 48.
    Doherty L, Gigas DC, Kesari S, et al. Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 2006;67: 156–158.PubMedGoogle Scholar
  49. 49.
    Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353: 2012–2024.PubMedGoogle Scholar
  50. 50.
    Fan QW, Cheng CK, Nicolaides TP, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 2007;67: 7960–7965.PubMedGoogle Scholar
  51. 51.
    Wang MY, Lu KV, Zhu S, et al. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 2006;66: 7864–7869.PubMedGoogle Scholar
  52. 52.
    Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005;23: 357–361.PubMedGoogle Scholar
  53. 53.
    Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 2008;5: e8.PubMedGoogle Scholar
  54. 54.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12: 9–22.PubMedGoogle Scholar
  55. 55.
    Nakamura JL, Garcia E, Pieper RO. S6K1 plays a key role in glial transformation. Cancer Res 2008;68: 6516–6523.PubMedGoogle Scholar
  56. 56.
    Carracedo A, Baselga J, Pandolfi PP. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORCl inhibitors. Cell Cycle 2008;7: 3805–3809.PubMedGoogle Scholar
  57. 57.
    Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORCl leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118: 3065–3074.PubMedGoogle Scholar
  58. 58.
    Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007;318: 287–290.PubMedGoogle Scholar
  59. 59.
    Hambardzumyan D, Becher OJ, Rosenblum MK, et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 2008;22: 436–448.PubMedGoogle Scholar
  60. 60.
    Johannessen TC, Bjerkvig R, Tysnes BB. DNA repair and cancer stem-like cells: potential partners in glioma drug resistance? Cancer Treat Rev 2008;34: 558–567.PubMedGoogle Scholar
  61. 61.
    Li Z, Wang H, Eyler CE, Rich JN. Turning cancer stem cells inside-out: an exploration of glioma stem cell signaling pathways. J Biol Chem 2009;Google Scholar
  62. 62.
    Bertrand J, Begaud-Grimaud G, Bessette B, et al. Cancer stem cells from human glioma cell line are resistant to Fas-induced apoptosis. Int J Oncol 2009;34: 717–727.PubMedGoogle Scholar
  63. 63.
    Solomon DA, Kim JS, Jenkins S, et al. Identification of p18INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer Res 2008;68: 2564–2569.PubMedGoogle Scholar
  64. 64.
    Yu Y, Jiang X, Schoch BS, et al. Aberrant splicing of cyclin-dependent kinase-associated protein phosphatase KAP increases proliferation and migration in glioblastoma. Cancer Res 2007;67: 130–138.PubMedGoogle Scholar
  65. 65.
    Glaser T, Wagenknecht B, Weiler M. Identification of p21 as a target of cycloheximide-mediated facilitation of CD95-mediated apoptosis in human malignant glioma cells. Oncogene 2001;20: 4757–4767.PubMedGoogle Scholar
  66. 66.
    Dinca EB, Lu KV, Sarkaria JN, et al. p53 Small-molecule inhibitor enhances temozolomide cytotoxic activity against intracranial glioblastoma xenografts. Cancer Res 2008;68: 10034–10039.PubMedGoogle Scholar
  67. 67.
    Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13: 84–88.PubMedGoogle Scholar
  68. 68.
    Gilbertson RJ, Rich JN. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 2007;7: 733–736.PubMedGoogle Scholar
  69. 69.
    Rich JN, Reardon DA, Peery T, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22: 133–142.PubMedGoogle Scholar
  70. 70.
    Brown PD, Krishnan S, Sarkaria JN, et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008;26: 5603–5609.PubMedGoogle Scholar
  71. 71.
    Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R. Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 2008;14: 957–960.PubMedGoogle Scholar
  72. 72.
    Wong TW, Lee FY, Yu C, et al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/ HER2 homodimer and heterodimer signaling. Clin Cancer Res 2006;12: 6186–6193.PubMedGoogle Scholar
  73. 73.
    Neyns B, Sadones J, Joosens E, et al. A multicenter stratified phase II study of cetuximab for the treatment of patients with recurrent high-grade glioma. J Clin Oncol Meet Abstr 2008;26: 2017 (abstract).Google Scholar
  74. 74.
    Cohenuram M, Saif MW. Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. Anticancer Drugs 2007;18: 7–15.PubMedGoogle Scholar
  75. 75.
    Bode U, Buchen S, Janssen G, et al. Results of a phase II trial of h-R3 monoclonal antibody (nimotuzumab) in the treatment of resistant or relapsed high-grade gliomas in children and adolescents. J Clin Oncol Meet Abstr 2006;24: 1522 (abstract).Google Scholar
  76. 76.
    Bode U, Buchen S, Warmuth-Metz M, et al. Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents. J Clin Oncol Meet Abstr 2007;25: 2006 (abstract).Google Scholar
  77. 77.
    Schmiedel J, Blaukat A, Li S, Knochel T, Ferguson KM. Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell 2008;13: 365–373.PubMedGoogle Scholar
  78. 78.
    Lammerts van Bueren JJ, Bleeker WK, Brannstrom A, et al. The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility. Proc Natl Acad Sci U S A 2008;105: 6109–6114.PubMedGoogle Scholar
  79. 79.
    Kuenen B, Witteveen E, Ruijter R, et al. A phase I study of IMC-11F8, a fully human anti-epidermal growth factor receptor (EGFR) IgGl monoclonal antibody in patients with solid tumors: interim results. ASCO Meet Abstr 2006;24: 3024 (abstract).Google Scholar
  80. 80.
    Tabemero J, Sastre Valera J, Delaunoit T, et al. A phase II multicenter study evaluating the efficacy and safety of IMC-11F8, a recombinant human IgGl anti-epidermal growth factor receptor (EGFR) monoclonal antibody (Mab), combined with 5-FU/FA and oxaliplatin (mFOLFOX-6) as first-line therapy. ASCO Meet Abstr 2008;26: 4066 (abstract).Google Scholar
  81. 81.
    Johns TG, Perera RM, Vernes SC, et al. The efficacy of epidermal growth factor receptor-specific antibodies against glioma xenografts is influenced by receptor levels, activation status, and heterodimerization. Clin Cancer Res 2007;13: 1911–1925.PubMedGoogle Scholar
  82. 82.
    Mineo JF, Bordron A, Quintin-Roue I, et al. Recombinant humanised anti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas. Br J Cancer 2004;91: 1195–1199.PubMedGoogle Scholar
  83. 83.
    Beltran PJ, Mitchell P, Moody G, et al. Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models. ASCO Meet Abstr 2008;26: 4617 (abstract).Google Scholar
  84. 84.
    Rowinsky EK, Youssoufian H, Tonra JR, et al. IMC-A12, a human IgGl monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res 2007;13: 5549s-5555s.PubMedGoogle Scholar
  85. 85.
    Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgGl monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol Meet Abstr 2007;25: 3505 (abstract).Google Scholar
  86. 86.
    Karp DD, Paz-Ares LG, Novello S, et al. High activity of the anti-IGF-IR antibody CP-751,871 in combination with paclitaxel and carboplatin in squamous NSCLC. ASCO Meet Abstr 2008;26: 8015 (abstract).Google Scholar
  87. 87.
    Cohen BD, Baker DA, Soderstrom C, et al. Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal anti-body CP-751,871. Clin Cancer Res 2005;11: 2063–2073.PubMedGoogle Scholar
  88. 88.
    Matsumoto K, Nakamura T, Sakai K. Hepatocyte growth factor and Met in tumor biology and therapeutic approach with NK4. Proteomics 2008;8: 3360–3370.PubMedGoogle Scholar
  89. 89.
    Mazzone M, Basilico C, Cavassa S, et al. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. J Clin Invest 2004;114: 1418–1432.PubMedGoogle Scholar
  90. 90.
    Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell 2004;6: 75–84.PubMedGoogle Scholar
  91. 91.
    Michieli P, Mazzone M, Basilico C, et al. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 2004;6: 61–73.PubMedGoogle Scholar
  92. 92.
    Compugen. CGEN-241: soluble valiants of MET. Available at: 20September%204%2008.pdf. Accessed May 29, 2009.Google Scholar
  93. 93.
    Kim KJ, Wang L, Su YC, et al. Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts. Clin Cancer Res 2006;12: 1292–1298.PubMedGoogle Scholar
  94. 94.
    Jun HT, Sun J, Rex K, et al. AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts. Clin Cancer Res 2007;13: 6735–6742.PubMedGoogle Scholar
  95. 95.
    Martens T, Schmidt NO, Eckerich C, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006;12: 6144–6152.PubMedGoogle Scholar
  96. 96.
    Tseng JR, Kang KW, Dandekar M, et al. Preclinical efficacy of the c-Met inhibitor CE-355621 in a U87 MG mouse xenograft model evaluated by 18F-FDG small-animal PET. J Nucl Med 2008;49: 129–134.PubMedGoogle Scholar
  97. 97.
    Petrelli A, Circosta P, Granziero L, et al. Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity. Proc Natl Acad Sci U S A 2006;103: 5090–5095.PubMedGoogle Scholar
  98. 98.
    Bellon SF, Kaplan-Lefko P, Yang Y, et al. c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J Biol Chem 2008;283: 2675–2683.PubMedGoogle Scholar
  99. 99.
    Garcia A, Rosen L, Cunningham CC, et al. Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose. J Clin Oncol Meet Abstr 2007;25: 3525 (abstract).Google Scholar
  100. 100.
    Yap TA, Harris D, Barriuso J, et al. Phase I trial to determine the dose range for the c-Met inhibitor ARQ 197 that inhibits c-Met and FAK phosphorylation, when administered by an oral twice-a-day schedule. J Clin Oncol Meet Abstr 2008;26: 3584 (abstract).Google Scholar
  101. 101.
    Camacho LH, Moulder SL, LoRusso PM, et al. First in human phase I study of MK-2461, a small molecule inhibitor of c-Met, for patients with advanced solid tumors. J Clin Oncol Meet Abstr 2008;26: 14657 (abstract).Google Scholar
  102. 102.
    Welsh J, Mahadevan D, Bearss D, Stea B. Sensitization of a glioblastoma multiforme (GBM) cell line by MP470: a novel c-Met antagonist. Int J Radiat Oncol Biol Phys 2007;69: S100 (abstract).Google Scholar
  103. 103.
    Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007;67: 4408–4417.PubMedGoogle Scholar
  104. 104.
    Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003;63: 7345–7355.PubMedGoogle Scholar
  105. 105.
    Berthou S, Aebersold DM, Schmidt LS, et al. The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene 2004;23: 5387–5393.PubMedGoogle Scholar
  106. 106.
    Sattler M, Pride YB, Ma P, et al. A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res 2003;63: 5462–5469.PubMedGoogle Scholar
  107. 107.
    Ross RW, Stein M, Sarantopoulos J, et al. A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC). J Clin Oncol Meet Abstr 2007;25: 15601 (abstract).Google Scholar
  108. 108.
    Salgia R, Sherman S, Hong DS, et al. A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol Meet Abstr 2008;26: 3522 (abstract).Google Scholar
  109. 109.
    Du J, Bernasconi P, Clauser KR, et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nat Biotechnol 2009;27: 77–83.PubMedGoogle Scholar
  110. 110.
    Raymond E, Brandes AA, Dittrich C, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group study. J Clin Oncol 2008;26: 4659–4665.PubMedGoogle Scholar
  111. 111.
    Reardon DA, Egorin MJ, Quinn JA, et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 2005;23: 9359–9368.PubMedGoogle Scholar
  112. 112.
    Wen PY, Yung WK, Lamborn KR, et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res 2006;12: 4899–4907.PubMedGoogle Scholar
  113. 113.
    Reardon DA, Egorin MJ, Desjardins A, et al. Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 2009;Google Scholar
  114. 114.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25: 4722–4729.PubMedGoogle Scholar
  115. 115.
    Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27: 740–745.PubMedGoogle Scholar
  116. 116.
    Gomez-Manzano C, Holash J, Fueyo J, et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol 2008;10: 940–945.PubMedGoogle Scholar
  117. 117.
    De Groot JF, Wen PY, Lamborn K, et al. Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601. J Clin Oncol Meet Abstr 2008;26: 2020 (abstract).Google Scholar
  118. 118.
    Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005;65: 4389–4400.PubMedGoogle Scholar
  119. 119.
    Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11: 83–95.PubMedGoogle Scholar
  120. 120.
    Podar K, Tonon G, Sattler M, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci U S A 2006;103: 19478–19483.PubMedGoogle Scholar
  121. 121.
    Adnane L, Trail PA, Taylor I, et al. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2006;407: 597–612.PubMedGoogle Scholar
  122. 122.
    Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62: 4645–4655.PubMedGoogle Scholar
  123. 123.
    Heymach JV, Paz-Ares L, De Braud F, et al. Randomized Phase II Study of Vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2008;26: 5407–5415.PubMedGoogle Scholar
  124. 124.
    Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib in meta-static hereditary medullary thyroid cancer: follow-up results of an open-label phase II trial. ASCO Meet Abstr 2007;25: 6018.Google Scholar
  125. 125.
    Kirkpatrick JP, Rich JN, Vredenburgh JJ, et al. Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG). ASCO Meet Abstr 2008;26: 2057 (abstract).Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2009

Authors and Affiliations

  • Tiffany T. Huang
    • 1
  • Shawn M. Sarkaria
    • 1
  • Timothy F. Cloughesy
    • 2
    • 3
  • Paul S. Mischel
    • 1
    • 3
  1. 1.Department of Pathology and Laboratory Medicine and Molecular & Medical PharmacologyUniversity of California, Los AngelesLos Angeles
  2. 2.Department of NeurologyUniversity of California, Los AngelesLos Angeles
  3. 3.Henry E. Singleton Brain Tumor Program, David Geffen School of MedicineUniversity of California, Los AngelesLos Angeles

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