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Neurology Research International
Volume 2012, Article ID 878425, 13 pages
http://dx.doi.org/10.1155/2012/878425
Review Article

Current Trends in Targeted Therapies for Glioblastoma Multiforme

Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

Received 1 August 2011; Revised 21 October 2011; Accepted 7 December 2011

Academic Editor: Jonas Sheehan

Copyright © 2012 Fumiharu Ohka et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. Stupp, W. P. Mason, M. J. van den Bent et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,” The New England Journal of Medicine, vol. 352, no. 10, pp. 987–996, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. R. Stupp, M. E. Hegi, W. P. Mason et al., “Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase IIII study: 5-year analysis of the EORTC-NCIC trial,” The Lancet Oncology, vol. 10, no. 5, pp. 459–466, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. J. P. Fruehauf, H. Brem, S. Brem et al., “In vitro drug response and molecular markers associated with drug resistance in malignant gliomas,” Clinical Cancer Research, vol. 12, no. 15, pp. 4523–4532, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. J. Ma, M. Murphy, P. J. O'Dwyer, E. Berman, K. Reed, and J. M. Gallo, “Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance,” Biochemical Pharmacology, vol. 63, no. 7, pp. 1219–1228, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Hermisson, A. Klumpp, W. Wick et al., “O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells,” Journal of Neurochemistry, vol. 96, no. 3, pp. 766–776, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. D. M. Kokkinakis, D. B. Bocangel, S. C. Schold, R. C. Moschel, and A. E. Pegg, “Thresholds of O6-alkylguanine-DNA alkyltransferase which significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide,” Clinical Cancer Research, vol. 7, no. 2, pp. 421–428, 2001. View at Google Scholar · View at Scopus
  7. K. S. Srivenugopal, X. H. Yuan, H. S. Friedman, and F. Ali-Osman, “Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumor cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea,” Biochemistry, vol. 35, no. 4, pp. 1328–1334, 1996. View at Google Scholar · View at Scopus
  8. M. Gilbert, “RTOG 0525: a randomized phase IIII trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM),” Journal of Clinical Oncology, vol. 29, supplement, 2011, Abstract no. 2006. View at Google Scholar
  9. R. S. Kerbel and B. A. Kamen, “The anti-angiogenic basis of metronomic chemotherapy,” Nature Reviews Cancer, vol. 4, no. 6, pp. 423–436, 2004. View at Google Scholar · View at Scopus
  10. F. Bertolini, S. Paul, P. Mancuso et al., “Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells,” Cancer Research, vol. 63, no. 15, pp. 4342–4346, 2003. View at Google Scholar · View at Scopus
  11. U. Emmenegger, S. Man, Y. Shaked et al., “A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens,” Cancer Research, vol. 64, no. 11, pp. 3994–4000, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. G. Bocci, G. Francia, S. Man, J. Lawler, and R. S. Kerbel, “Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 12917–12922, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. J. R. Perry, K. Bélanger, W. P. Mason et al., “Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study,” Journal of Clinical Oncology, vol. 28, no. 12, pp. 2051–2057, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. W. Wick, “NOA-08 randomized phase IIII trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem),” Journal of Clinical Oncology, vol. 28, supplement, 2010, Abstract no. LBA2001. View at Google Scholar
  15. O. Chinot, “TEMOBIC: a ANOCEF phase II study of BCNU and temozolomide (TMZ) combination prior to radiotherapy (RT) in anaplasic oligodendroglial gliomas (AOG),” Journal of Clinical Oncology, vol. 29, supplement, 2011, Abstract no. 2034. View at Google Scholar
  16. L. Liu and S. L. Gerson, “Targeted modulation of MGMT: clinical implications,” Clinical Cancer Research, vol. 12, no. 2, pp. 328–331, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. T. Kanzawa, J. Bedwell, Y. Kondo, S. Kondo, and I. M. Germano, “Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide,” Journal of Neurosurgery, vol. 99, no. 6, pp. 1047–1052, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. J. A. Quinn, J. Pluda, M. E. Dolan et al., “Phase II trial of carmustine plus O6-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma,” Journal of Clinical Oncology, vol. 20, no. 9, pp. 2277–2283, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. J. A. Quinn, A. Desjardins, J. Weingart et al., “Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma,” Journal of Clinical Oncology, vol. 23, no. 28, pp. 7178–7187, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. D. A. Reardon, K. L. Fink, T. Mikkelsen et al., “Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme,” Journal of Clinical Oncology, vol. 26, no. 34, pp. 5610–5617, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. B. Nabors, “Cilengitide in patients with newly diagnosed patients with glioblastoma multiforme and unmethylated MGMG gene promoter: safety run-in results from a randomized controlled phase II study (CORE),” Journal of Neuro-Oncology, vol. 12, p. iv75, 2010, Abstract no. OT-26. View at Google Scholar
  22. M. Chawla-Sarkar, D. J. Lindner, Y. F. Liu et al., “Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis,” Apoptosis, vol. 8, no. 3, pp. 237–249, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Wakabayashi, N. Hatano, Y. Kajita et al., “Initial and maintenance combination treatment with interferon-β, MCNU (Ranimustine), and radiotherapy for patients with previously untreated malignant glioma,” Journal of Neuro-Oncology, vol. 49, no. 1, pp. 57–62, 2000. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Natsume, D. IshII, T. Wakabayashi et al., “IFN-β down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide,” Cancer Research, vol. 65, no. 17, pp. 7573–7579, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. A. Natsume, T. Wakabayashi, D. IshII et al., “A combination of IFN-β and temozolomide in human glioma xenograft models: implication of p53-mediated MGMT downregulation,” Cancer Chemotherapy and Pharmacology, vol. 61, no. 4, pp. 653–659, 2008. View at Publisher · View at Google Scholar · View at PubMed
  26. J. J. Vredenburgh, A. Desjardins, J. E. Herndon et al., “Bevacizumab plus irinotecan in recurrent glioblastoma multiforme,” Journal of Clinical Oncology, vol. 25, no. 30, pp. 4722–4729, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. H. S. Friedman, M. D. Prados, P. Y. Wen et al., “Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma,” Journal of Clinical Oncology, vol. 27, no. 28, pp. 4733–4740, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. M. C. Chamberlain, “Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas,” Cancer, vol. 116, no. 17, pp. 3988–3999, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. A. D. Norden, J. Drappatz, and P. Y. Wen, “Novel anti-angiogenic therapies for malignant gliomas,” The Lancet Neurology, vol. 7, no. 12, pp. 1152–1160, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. M. Gruber, “Bevacizumab in combination with radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma: update progression-free survival, overall survival, and toxicity,” Journal of Clinical Oncology, vol. 27, supplement, p. 15s, 2009, abstract no. 2017. View at Google Scholar
  31. O. L. Chinot, T. de La Motte Rouge, N. Moore et al., “AVAglio: phase 3 trial of bevacizumab plus temozolomide and radiotherapy in newly diagnosed glioblastoma multiforme,” Advances in Therapy, vol. 28, no. 4, pp. 334–340, 2011. View at Publisher · View at Google Scholar · View at PubMed
  32. O. Keunen, M. Johansson, A. Oudin et al., “Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 9, pp. 3749–3754, 2011. View at Publisher · View at Google Scholar · View at PubMed
  33. T. T. Batchelor, D. G. Duda, E. di Tomaso et al., “Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma,” Journal of Clinical Oncology, vol. 28, no. 17, pp. 2817–2823, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. T. T. Batchelor, “The efficacy of cediranib as monotherapy and in combination with lomustine compared to lomustine alone in patients with recurrent glioblastoma: a phase IIII randomized study,” Neuro-Oncology, vol. 12, p. iv75, 2010, Abstract no. OT-25. View at Google Scholar
  35. M. Katoh and M. Katoh, “WNT signaling pathway and stem cell signaling network,” Clinical Cancer Research, vol. 13, no. 14, pp. 4042–4045, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. C. K. Cheng, Q. W. Fan, and W. A. Weiss, “PI3K signaling in glioma—animal models and therapeutic challenges,” Brain Pathology, vol. 19, no. 1, pp. 112–120, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. H. Ohgaki and P. Kleihues, “Genetic alterations and signaling pathways in the evolution of gliomas,” Cancer Science, vol. 100, no. 12, pp. 2235–2241, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. Q. W. Fan and W. A. Weiss, “Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance,” Current Topics in Microbiology and Immunology, vol. 347, pp. 279–296, 2010. View at Google Scholar
  39. H. Ohgaki, P. Dessen, B. Jourde et al., “Genetic pathways to glioblastoma: a population-based study,” Cancer Research, vol. 64, no. 19, pp. 6892–6899, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. L. Frederick, X. Y. Wang, G. Eley, and C. D. James, “Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas,” Cancer Research, vol. 60, no. 5, pp. 1383–1387, 2000. View at Google Scholar · View at Scopus
  41. A. M. Martelli, C. Evangelisti, F. Chiarini, and J. A. McCubrey, “The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients,” Oncotarget, vol. 1, no. 2, pp. 89–103, 2010. View at Google Scholar
  42. T. L. Yuan and L. C. Cantley, “PI3K pathway alterations in cancer: variations on a theme,” Oncogene, vol. 27, no. 41, pp. 5497–5510, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. P. C. De Witt Hamer, “Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies,” Neuro-Oncology, vol. 12, no. 3, pp. 304–316, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. J. N. Rich, D. A. Reardon, T. Peery et al., “Phase II trial of gefitinib in recurrent glioblastoma,” Journal of Clinical Oncology, vol. 22, no. 1, pp. 133–142, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. M. J. van den Bent, A. A. Brandes, R. Rampling et al., “Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034,” Journal of Clinical Oncology, vol. 27, no. 8, pp. 1268–1274, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. D. Strumberg, B. Schultheis, M. E. Scheulen et al., “Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer,” Investigational New Drugs. In press. View at Publisher · View at Google Scholar · View at PubMed
  47. J. H. Uhm, K. V. Ballman, W. Wu et al., “Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074,” International Journal of Radiation Oncology, Biology, Physics, vol. 80, pp. 347–353, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. D. A. Reardon, A. Desjardins, J. J. Vredenburgh et al., “Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma,” Journal of Neuro-Oncology, vol. 96, no. 2, pp. 219–230, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. F. Bach, “Current status of a phase III trial of nimotuzumab (ti-EGF-R) in newly diagnosed glioblastoma,” Journal of Clinical Oncology, vol. 29, supplement, 2011, Abstract no. 2059. View at Publisher · View at Google Scholar · View at PubMed
  50. R. Lai, “Final analysis of act IIII: a phase II trial of PF04948568 (CDX-110) in combination with temozolomide (TMZ) in patients (PTS) with newly diagnosed glioblastoma (GBM),” Neuro-Oncology, vol. 12, p. iv76, 2010, Abstract no. OT-31. View at Google Scholar
  51. D. D. Eisenstat, “A phase II study of daily afatinib (BIBW 2992) with or without temozolomide (21/28 days) in the treatment of patients with recurrent glioblastoma,” Journal of Clinical Oncology, vol. 29, supplement, 2011, Abstract no. 2010. View at Google Scholar
  52. B. J. Druker, M. Talpaz, D. J. Resta et al., “Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia,” The New England Journal of Medicine, vol. 344, no. 14, pp. 1031–1037, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Verweij, A. Van Oosterom, J. Y. Blay et al., “Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study,” European Journal of Cancer, vol. 39, no. 14, pp. 2006–2011, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. G. D. Demetri, M. Von Mehren, C. D. Blanke et al., “Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors,” The New England Journal of Medicine, vol. 347, no. 7, pp. 472–480, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. P. Y. Wen, W. K. A. Yung, K. R. Lamborn et al., “Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08,” Clinical Cancer Research, vol. 12, no. 16, pp. 4899–4907, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. E. Razis, P. Selviaridis, S. Labropoulos et al., “Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment,” Clinical Cancer Research, vol. 15, no. 19, pp. 6258–6266, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. T. Kreisl, “A phase II trial of sunitinib in the treatment of recurrent glioblastoma (GBM),” Neuro-Oncology, vol. 12, p. iv71, 2010, Abstract no. OT-12. View at Google Scholar
  58. C. Lu-Emerson, A. D. Norden, J. Drappatz et al., “Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure,” Journal of Neuro-Oncology, vol. 104, no. 1, pp. 287–291, 2011. View at Publisher · View at Google Scholar · View at PubMed
  59. P. Workman, P. A. Clarke, F. I. Raynaud, and R. L. M. Van Montfort, “Drugging the PI3 kinome: from chemical tools to drugs in the clinic,” Cancer Research, vol. 70, no. 6, pp. 2146–2157, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. B. M. Slomovitz, K. H. Lu, T. Johnston et al., “A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma,” Cancer, vol. 116, no. 23, pp. 5415–5419, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. E. Calvo, M. V. Bolós, and E. Grande, “Multiple roles and therapeutic implications of Akt signaling in cancer,” OncoTargets and Therapy, vol. 2, pp. 135–150, 2009. View at Google Scholar · View at Scopus
  62. H. Azim, H. A. Azim, and B. Escudier, “Targeting mTOR in cancer: renal cell is just a beginning,” Targeted Oncology, vol. 5, pp. 269–280, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. S. A. Grossman, X. Ye, M. Chamberlain et al., “Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial,” Journal of Clinical Oncology, vol. 27, no. 25, pp. 4155–4161, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. F. M. Iwamoto, T. N. Kreisl, L. Kim et al., “Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas,” Cancer, vol. 116, no. 7, pp. 1776–1782, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. E. Galanis, K. A. Jaeckle, M. J. Maurer et al., “Phase II trial of Vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study,” Journal of Clinical Oncology, vol. 27, no. 12, pp. 2052–2058, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. P. Y. Wen, “Phase I study of vorinostat in combination with temozolomide in patients with malignant gliomas,” Journal of Clinical Oncology, vol. 29, supplement, 2011, Abstract no. 2032. View at Google Scholar
  67. S. K. Singh, C. Hawkins, I. D. Clarke et al., “Identification of human brain tumour initiating cells,” Nature, vol. 432, no. 7015, pp. 396–401, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. J. Lee, M. J. Son, K. Woolard et al., “Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells,” Cancer Cell, vol. 13, no. 1, pp. 69–80, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. A. Eramo, L. Ricci-Vitiani, A. Zeuner et al., “Chemotherapy resistance of glioblastoma stem cells,” Cell Death and Differentiation, vol. 13, no. 7, pp. 1238–1241, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. A. Natsume, S. Kinjo, K. Yuki et al., “Glioma-initiating cells and molecular pathology: implications for therapy,” Brain Tumor Pathology, vol. 28, no. 1, pp. 1–12, 2011. View at Publisher · View at Google Scholar · View at PubMed
  71. M. Groszer, R. Erickson, D. D. Scripture-Adams et al., “Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo,” Science, vol. 294, no. 5549, pp. 2186–2189, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. A. M. Bleau, D. Hambardzumyan, T. Ozawa et al., “PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells,” Cell Stem Cell, vol. 4, no. 3, pp. 226–235, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. C. Gregorian, J. Nakashima, J. L. Belle et al., “Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis,” Journal of Neuroscience, vol. 29, no. 6, pp. 1874–1886, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. C. H. Kwon, D. Zhao, J. Chen et al., “Pten haploinsufficiency accelerates formation of high-grade astrocytomas,” Cancer Research, vol. 68, no. 9, pp. 3286–3294, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. A. Xiao, H. Wu, P. P. Pandolfi, D. N. Louis, and T. Van Dyke, “Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation,” Cancer Cell, vol. 1, no. 2, pp. 157–168, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. V. Clement, P. Sanchez, N. de Tribolet, I. Radovanovic, and A. Ruiz i Altaba, “HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity,” Current Biology, vol. 17, no. 2, pp. 165–172, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. P. M. LoRusso, C. M. Rudin, J. C. Reddy et al., “Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors,” Clinical Cancer Research, vol. 17, no. 8, pp. 2502–2511, 2011. View at Publisher · View at Google Scholar · View at PubMed
  78. X. Fan, L. Khaki, T. S. Zhu et al., “NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts,” Stem Cells, vol. 28, no. 1, pp. 5–16, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. M. M. Lino, A. Merlo, and J. L. Boulay, “Notch signaling in glioblastoma: a developmental drug target?” BMC Medicine, vol. 8, article 72, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. A. Pannuti, K. Foreman, P. Rizzo et al., “Targeting Notch to target cancer stem cells,” Clinical Cancer Research, vol. 16, no. 12, pp. 3141–3152, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. W. J. Nelson and R. Nusse, “Convergence of Wnt, β-Catenin, and Cadherin pathways,” Science, vol. 303, no. 5663, pp. 1483–1487, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. F. Takahashi-Yanaga and M. Kahn, “Targeting Wnt signaling: can we safely eradicate cancer stem cells?” Clinical Cancer Research, vol. 16, no. 12, pp. 3153–3162, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. M. W. Pitz, A. Desai, S. A. Grossman, and J. O. Blakeley, “Tissue concentration of systemically administered antineoplastic agents in human brain tumors,” Journal of Neuro-Oncology, vol. 104, no. 3, pp. 629–638, 2011. View at Publisher · View at Google Scholar · View at PubMed
  84. M. Westphal, Z. Ram, V. Riddle, D. Hilt, and E. Bortey, “Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial,” Acta Neurochirurgica, vol. 148, no. 3, pp. 269–275, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. S. Valtonen, U. Timonen, P. Toivanen et al., “Interstitial chemotherapy with carmustine-loaded polymers for high- grade gliomas: a randomized double-blind study,” Neurosurgery, vol. 41, no. 1, pp. 44–49, 1997. View at Publisher · View at Google Scholar · View at Scopus
  86. J. Plowman, W. R. Waud, A. D. Koutsoukos, L. V. Rubinstein, T. D. Moore, and M. R. Grever, “Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1- nitrosourea,” Cancer Research, vol. 54, no. 14, pp. 3793–3799, 1994. View at Google Scholar · View at Scopus
  87. H. C. Bock, M. J. A. Puchner, F. Lohmann et al., “First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience,” Neurosurgical Review, vol. 33, no. 4, pp. 441–449, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. K. S. Bankiewicz, J. L. Eberling, M. Kohutnicka et al., “Convection-enhanced delivery of AAV vector in Parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach,” Experimental Neurology, vol. 164, no. 1, pp. 2–14, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. P. Hadaczek, M. Kohutnicka, M. T. Krauze et al., “Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain,” Human Gene Therapy, vol. 17, no. 3, pp. 291–302, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. M. T. Krauze, S. R. Vandenberg, Y. Yamashita et al., “Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective,” Experimental Neurology, vol. 210, no. 2, pp. 638–644, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. T. A. Wynn, “IL-13 effector functions,” Annual Review of Immunology, vol. 21, pp. 425–456, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. W. Debinski, N. I. Obiri, S. K. Powers, I. Pastan, and R. K. Puri, “Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin,” Clinical Cancer Research, vol. 1, no. 11, pp. 1253–1258, 1995. View at Google Scholar · View at Scopus
  93. M. Mut, J. H. Sherman, M. E. Shaffrey, and D. Schiff, “Cintredekin besudotox in treatment of malignant glioma,” Expert Opinion on Biological Therapy, vol. 8, no. 6, pp. 805–812, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. S. Kunwar, S. M. Chang, M. D. Prados et al., “Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies,” Neurosurgical Focus, vol. 20, no. 4, p. E15, 2006. View at Google Scholar · View at Scopus
  95. C. Kjellman, S. P. Olofsson, O. Hansson et al., “Expression of TGF-β isoforms, TGF-β receptors, and Smad molecules at different stages of human glioma,” International Journal of Cancer, vol. 89, no. 3, pp. 251–258, 2000. View at Publisher · View at Google Scholar · View at Scopus
  96. P. Hau, P. Jachimczak, R. Schlingensiepen et al., “Inhibition of TGF-β2 with ap 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies,” Oligonucleotides, vol. 17, no. 2, pp. 201–212, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. M. D. Hjelmeland, A. B. Hjelmeland, S. Sathornsumetee et al., “SB-431542, a small molecule transforming growth factor-β-receptor antagonist, inhibits human glioma cell line proliferation and motility,” Molecular Cancer Therapeutics, vol. 3, no. 6, pp. 737–745, 2004. View at Google Scholar · View at Scopus
  98. U. Naumann, P. Maass, A. K. Gleske, S. Aulwurm, M. Weller, and G. Eisele, “Glioma gene therapy with soluble transforming growth factor-β receptors II and IIII,” International Journal of Oncology, vol. 33, no. 4, pp. 759–765, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. T. Schneider, A. Becker, K. Ringe, A. Reinhold, R. Firsching, and B. A. Sabel, “Brain tumor therapy by combined vaccination and antisense oligonucleotide delivery with nanoparticles,” Journal of Neuroimmunology, vol. 195, no. 1-2, pp. 21–27, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. T. T. Tran, M. Uhl, Y. M. Jing et al., “Inhibiting TGF-β signaling restores immune surveillance in the SMA-560 glioma model,” Neuro-Oncology, vol. 9, no. 3, pp. 259–270, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. M. Uhl, S. Aulwurm, J. Wischhusen et al., “SD-208, a novel transforming growth factor β receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo,” Cancer Research, vol. 64, no. 21, pp. 7954–7961, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. K. H. Schlingensiepen, R. Schlingensiepen, A. Steinbrecher et al., “Targeted tumor therapy with the TGF-β2 antisense compound AP 12009,” Cytokine and Growth Factor Reviews, vol. 17, no. 1-2, pp. 129–139, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  103. L. Valliéres, “Trabedersen, a TGFβ2-specific antisense oligonucleotide for the treatment of malignant gliomas and other tumors overexpressing TGFβ2,” IDrugs, vol. 12, no. 7, pp. 445–453, 2009. View at Google Scholar
  104. U. Bogdahn, P. Hau, G. Stockhammer et al., “Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study,” Neuro-Oncology, vol. 13, no. 1, pp. 132–142, 2011. View at Publisher · View at Google Scholar · View at PubMed
  105. R. McLendon, A. Friedman, D. Bigner et al., “Comprehensive genomic characterization defines human glioblastoma genes and core pathways,” Nature, vol. 455, no. 7216, pp. 1061–1068, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. D. W. Parsons, S. Jones, X. Zhang et al., “An integrated genomic analysis of human glioblastoma multiforme,” Science, vol. 321, no. 5897, pp. 1807–1812, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. H. Noushmehr, D. J. Weisenberger, K. Diefes et al., “Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma,” Cancer Cell, vol. 17, no. 5, pp. 510–522, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. T. M. Kim, W. Huang, R. Park, P. J. Park, and M. D. Johnson, “A developmental taxonomy of glioblastoma defined and maintained by microRNAs,” Cancer Research, vol. 71, no. 9, pp. 3387–3399, 2011. View at Publisher · View at Google Scholar · View at PubMed
  109. R. G. W. Verhaak, K. A. Hoadley, E. Purdom et al., “Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1,” Cancer Cell, vol. 17, no. 1, pp. 98–110, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus