Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Development of novel targeted therapies in the treatment of malignant glioma

Nature Reviews Drug Discovery volume 3, pages 430–446 (2004)Cite this article

Key Points

  • Gliomas are strikingly heterogeneous tumours in terms of their pathology and gene expression, even within a single tumour. But despite this variability, common alterations within specific cellular signal transduction pathways or cellular functions can be found in most malignant gliomas, some of which represent opportunities for therapeutic intervention.

  • This article focuses on molecularly targeted therapies for malignant glioma, in particular, those aimed at growth factor receptors (including the epidermal growth factor receptor, the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor), the RAS/RAF/MAPK/ERK pathway and mammalian target of rapamycin.

  • Clinical trial results so far are presented, and key issues in the clinical development of these therapies are discussed, including drug delivery, monitoring of activity and the use of drug combinations.

Abstract

Malignant gliomas are highly lethal tumours despite maximal therapy. Traditional treatments for these cancers — which rely on nonspecific, cytotoxic approaches that generally act through damaging DNA — have a marginal impact on patient survival. However, advances in the understanding of the molecular biology underlying glioma pathogenesis have revealed abnormalities in a set of common cellular pathways and functions among the majority of these tumours that are now being targeted by novel agents in preclinical and clinical development. Such molecularly targeted agents might offer the promise of improved tumour control without substantial toxicity. Still, significant challenges in their development remain: the inability to predict tumour response and limitations of drug delivery into the tumour. Two essential aspects of glioma therapy remain to be achieved: local control of the primary tumour and blockade of tumour-cell invasion of normal brain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular pathways to glioblastoma formation.
Figure 2: Cellular pathways that are altered in gliomas.
Figure 3: Targeting mitogenic pathways in gliomas.
Figure 4: Growth-factor receptor targeting.
Figure 5: Small-molecule EGFR tyrosine kinase inhibitor maintains control of glioblastoma.
Figure 6: Near-complete response of glioblastoma patient treated with transforming growth factor-α–toxin chimaera (TP-38).
Figure 7: Small-molecule VEGFR2 tyrosine kinase inhibitor induces tumour response.
Figure 8: The transforming growth factor-β signal transduction pathways.

Similar content being viewed by others

References

  1. Legler, J. M. et al. Brain and other central nervous system cancers: recent trends in incidence and mortality. J. Natl Cancer Inst. 91, 2050A–2051A (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Wrensch, M., Minn, Y., Chew, T., Bondy, M. & Berger, M. S. Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro-oncol. 4, 278–299 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ron, E. et al. Tumors of the brain and nervous system after radiotherapy in childhood. N. Engl. J. Med. 319, 1033–1039 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Kleihues, P. & Cavenee, W. K. Pathology and Genetics of Tumors of the Nervous System (IARC, Lyon, 2000). Excellent overview of the pathology, epidemiology and biology of nervous system neoplasms.

    Google Scholar 

  5. Burger, P. C., Vogel, F. S. & Green, S. B. Glioblastoma multiforme and anaplastic astrocytoma: pathologic criteria and prognostic implications. Cancer 56, 1106–1111 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Bauman, G. et al. Pretreatment factors predict overall survival for patients with low-grade glioma: a recursive partitioning analysis. Int. J. Radiat. Oncol. Biol. Phys. 45, 923–929 (1999). Useful analysis of patient characteristics that heavily influence patient outcome. Clinical trials in neuro-oncology must incorporate these factors in their design.

    Article  CAS  PubMed  Google Scholar 

  7. Pignatti, F. et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J. Clin. Oncol. 20, 2076–2084 (2002).

    Article  PubMed  Google Scholar 

  8. Keles, G. E., Lamborn, K. R. & Berger, M. S. Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome. J. Neurosurg. 95, 735–745 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Shaw, E. et al. Prospective randomized trial of low-versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J. Clin. Oncol. 20, 2267–2276 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Quinn, J. A. et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J. Clin. Oncol. 21, 646–651 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Scott, C. B. et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int. J. Radiat. Oncol. Biol. Phys. 40, 51–55 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Davis, F. G., McCarthy, B. J., Freels, S., Kupelian V. & Bondy, M. L. The conditional probability of survival of patients with primary malignant brain tumors. Surveillance, epidemiology, and end results (SEER) data. Cancer 85, 485–491 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Behin, A., Hoang-Xuan, K., Carpentier, A. F. & Delattre, J. Y. Primary brain tumours in adults. Lancet 361, 323–331 (2003). Overview of glioma and lymphoma management.

    Article  PubMed  Google Scholar 

  14. Sawaya, R. Extent of resection in malignant gliomas: a critical summary. J. Neurooncol. 42, 303–305 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Stewart, L. A. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359, 1011–1018 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Wallner, K. E., Galicich, J. H., Krol, G., Arbit, E. & Malkin, M. G. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int. J. Radiat. Oncol. Biol. Phys. 16, 1405–1409 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Senger, D., Cairncross, J. G. & Forsyth, P. A. Long-term survivors of glioblastoma: statistical aberration or important unrecognized molecular subtype? Cancer J. 9, 214–221 (2003).

    Article  PubMed  Google Scholar 

  18. Smith, J. S. et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J. Clin. Oncol. 18, 636–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Cairncross, J. G. et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendroglioma. J. Natl Cancer Inst. 90, 1473–1479 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000). A seminal review of cancer biology.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. von Deimling, A. et al. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol. 3, 19–26 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. van Meyel, D. J. et al. p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J. Natl Cancer Inst. 86, 1011–1017 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Bogler, O., Huang, H. J. & Cavenee, W. K. Loss of wild-type p53 bestows a growth advantage on primary cortical astrocytes and facilitates their in vitro transformation. Cancer Res. 55, 2746–2751 (1995).

    CAS  PubMed  Google Scholar 

  26. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. von Deimling, A. et al. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res. 52, 2987–2990 (1992).

    CAS  PubMed  Google Scholar 

  28. Sidransky, D. et al. Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355, 846–847 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Rasheed, B. K. et al. Alterations of the TP53 gene in human gliomas. Cancer Res. 54, 1324–1330 (1994).

    CAS  PubMed  Google Scholar 

  30. Sung, T. et al. Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol. 10, 249–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Momand, J. et al. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299–303 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Biernat, W., Kleihues, P., Yonekawa, Y. & Ohgaki, H. Amplification and overexpression of MDM2 in primary (de novo) glioblastomas. J. Neuropathol. Exp. Neurol. 56, 180–185 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Pomerantz, J. et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92, 713–723 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Honda, R. & Yasuda, H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 18, 22–27 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nakamura, M. et al. p14ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol. 11, 159–168 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Newcomb, E. W., Alonso, M., Sung, T. & Miller, D. C. Incidence of p14ARF gene deletion in high-grade adult and pediatric astrocytomas. Hum. Pathol. 31, 115–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Ichimura, K. et al. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1–S transition control gene abnormalities. Cancer Res. 60, 417–424 (2000).

    CAS  PubMed  Google Scholar 

  40. Fulci, G. et al. p53 gene mutation and ink4a-arf deletion appear to be two mutually exclusive events in human glioblastoma. Oncogene 19, 3816–3822 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Biernat, W. et al. Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 94, 303–309 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Ichimura, K., Schmidt, E. E., Goike, H. M. & Collins, V. P. Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13, 1065–1072 (1996).

    CAS  PubMed  Google Scholar 

  44. Jen, J. et al. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 54, 6353–6358 (1994).

    CAS  PubMed  Google Scholar 

  45. Ueki, K. et al. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 56, 150–153 (1996).

    CAS  PubMed  Google Scholar 

  46. Schmidt, E. E., Ichimura, K., Reifenberger, G. & Collins, V. P. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 54, 6321–6324 (1994).

    CAS  PubMed  Google Scholar 

  47. He, J., Olson, J. J. & James, C. D. Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. Cancer Res. 55, 4833–4836 (1995).

    CAS  PubMed  Google Scholar 

  48. Schmidt, E. E. et al. Infrequent methylation of CDKN2A(MTS1/p16) and rare mutation of both CDKN2A and CDKN2B(MTS2/p15) in primary astrocytic tumours. Br. J. Cancer 75, 2–8 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kapoor, G. S. & O'Rourke, D. M. Mitogenic signaling cascades in glial tumors. Neurosurgery 52, 1425–1434 (2003).

    Article  PubMed  Google Scholar 

  50. Libermann, T. A. et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313, 144–147 (1985). Early recognition of EGFR alterations in gliomas.

    Article  CAS  PubMed  Google Scholar 

  51. Humphrey, P. A. et al. Amplification and expression of the epidermal growth factor receptor gene in human glioma xenografts. Cancer Res. 48, 2231–2238 (1988).

    CAS  PubMed  Google Scholar 

  52. Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).

    CAS  PubMed  Google Scholar 

  53. Frederick, L., Wang, X. Y., Eley, G. & James, C. D. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 60, 1383–1387 (2000).

    CAS  PubMed  Google Scholar 

  54. Fujimoto, M. et al. Expression of three viral oncogenes (v-sis, v-myc, v-fos) in primary human brain tumors of neuroectodermal origin. Neurology 38, 289–293 (1988).

    Article  CAS  PubMed  Google Scholar 

  55. Nister, M. et al. Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-α and their receptors in human malignant glioma cell lines. Cancer Res. 48, 3910–3918 (1988). Original report of the expression of PDGF pathway components in malignant gliomas.

    CAS  PubMed  Google Scholar 

  56. Hermanson, M. et al. Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res. 52, 3213–3219 (1992).

    CAS  PubMed  Google Scholar 

  57. Guha, A. et al. Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int. J. Cancer 60, 168–173 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Hermanson, M. et al. Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor α receptor expression in human malignant gliomas. Cancer Res. 56, 164–171 (1996).

    CAS  PubMed  Google Scholar 

  59. Gammeltoft, S. et al. Expression of two types of receptor for insulin-like growth factors in human malignant glioma. Cancer Res. 48, 1233–1237 (1988).

    CAS  PubMed  Google Scholar 

  60. Rosen, E. M. et al. Scatter factor expression and regulation in human glial tumors. Int. J. Cancer. 67, 248–255 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Plate, K. H., Breier, G., Weich, H. A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Berkman, R. A. et al. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J. Clin. Invest. 91, 153–159 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Constam, D. B. et al. Differential expression of transforming growth factor-β1,-β2, and -β3 by glioblastoma cells, astrocytes, and microglia. J. Immunol. 148, 1404–1410 (1992).

    CAS  PubMed  Google Scholar 

  64. Kjellman, C. et al. Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma. Int. J. Cancer 89, 251–258 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nature Rev. Cancer 3, 11–22 (2003).

    Article  CAS  Google Scholar 

  66. Burgart, L. J., Robinson, R. A., Haddad, S. F. & Moore, S. A. Oncogene abnormalities in astrocytomas: EGF-R gene alone appears to be more frequently amplified and rearranged compared with other protooncogenes. Mod. Pathol. 4, 183–186 (1991).

    CAS  PubMed  Google Scholar 

  67. Guha, A. et al. Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15, 2755–2765 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase–Akt pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  69. Choe, G. et al. Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 63, 2742–2746 (2003).

    CAS  PubMed  Google Scholar 

  70. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997). This and the following reports first identified PTEN as an important novel tumour suppressor gene.

    Article  CAS  PubMed  Google Scholar 

  71. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Lin, H. et al. Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin. Cancer Res. 4, 2447–2454 (1998).

    CAS  PubMed  Google Scholar 

  73. Sano, T. et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res. 59, 1820–1824 (1999).

    CAS  PubMed  Google Scholar 

  74. Raffel, C. et al. Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. Clin. Cancer Res. 5, 4085–4090 (1999).

    CAS  PubMed  Google Scholar 

  75. Myers, M. P. et al. PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc. Natl Acad. Sci. USA 94, 9052–9057 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tamura, M. et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280, 1614–1617 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Myers, M. P. et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc. Natl Acad. Sci. USA 95, 13513–13518 (1998). This and the following two reports outlined surprising roles for PTEN regulating phospholipids as crucial in its tumour-suppressive functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu, X. et al. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc. Natl Acad. Sci. USA 95, 15587–15591 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Su, J. D., Mighto, L. D., Donner, D. B. & Durden, D. L. PTEN and phosphatidylinositol 3′-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res. 63, 3585–3592 (2003).

    CAS  PubMed  Google Scholar 

  81. Abe, T. et al. PTEN decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli. Cancer Res. 63, 2300–2305 (2003).

    CAS  PubMed  Google Scholar 

  82. Koul, D. et al. Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20, 6669–6678 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Kuriyama, H. et al. Prognostic significance of an apoptotic index and apoptosis/proliferation ratio for patients with high-grade astrocytomas. Neuro-oncol. 4, 179–186 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Heesters, M. A., Koudstaal, J., Go, K. G. & Molenaar, W. M. Analysis of proliferation and apoptosis in brain gliomas: prognostic and clinical value. J. Neurooncol. 44, 255–266 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Trepel, M. et al. Chemosensitivity of human malignant glioma: modulation by p53 gene transfer. J. Neurooncol. 39, 19–32 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Vogelbaum, M. A. et al. Transfection of C6 glioma cells with the bax gene and increased sensitivity to treatment with cytosine arabinoside. J. Neurosurg. 88, 99–105 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Nagane, M. et al. Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res. 60, 847–853 (2000).

    CAS  PubMed  Google Scholar 

  88. Fulda, S., Wick, W., Weller, M. & Debatin, K. M. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nature Med. 8, 808–815 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Shingu, T. et al. Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells. Cancer Res. 63, 4044–4047 (2003).

    CAS  PubMed  Google Scholar 

  90. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  PubMed  Google Scholar 

  91. Hahn, W. C. Role of telomeres and telomerase in the pathogenesis of human cancer. J. Clin. Oncol. 21, 2034–2043 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Morin, G. B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529 (1989).

    Article  CAS  PubMed  Google Scholar 

  93. Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785–795 (1997). Initial report of the cloning of the human telomerase catalytic subunit that is expressed in many cancers.

    Article  CAS  PubMed  Google Scholar 

  94. Kim, N. -W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    Article  CAS  PubMed  Google Scholar 

  95. Langford, L. A. et al. Telomerase activity in human brain tumours. Lancet 346, 1267–1268 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Hiraga, S. et al. Telomerase activity and alterations in telomere length in human brain tumors. Cancer Res. 58, 2117–2125 (1998).

    CAS  PubMed  Google Scholar 

  97. Hakin-Smith, V. et al. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 361, 836–838 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Yamaguchi, F. et al. Anti-telomerase therapy suppressed glioma proliferation. Oncol. Rep. 6, 773–776 (1999).

    CAS  PubMed  Google Scholar 

  99. Holland, E. C., Hively, W. P., DePinho, R. A. & Varmus, H. E. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev. 12, 3675–3685 (1998). One of several papers delineating an elegant malleable model of malignant glioma formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55–57 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Dai, C. et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 15, 1913–1925 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xiao, A. et al. Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1, 157–168 (2002). PTEN loss might function in a tissue-specific fashion to increase tumour malignancy.

    Article  CAS  PubMed  Google Scholar 

  103. Weiss, W. A. et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res. 63, 1589–1595 (2003).

    CAS  PubMed  Google Scholar 

  104. Bachoo, R. M. 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 1, 269–277 (2002). Report suggesting that differentiated astrocytes might be driven to dedifferentiate and transform into gliomas.

    Article  CAS  PubMed  Google Scholar 

  105. Reilly, K. M. et al. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genet. 26, 109–113 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Vogel, K. S. et al. Mouse tumor model for neurofibromatosis type 1. Science 286, 2176–2179 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ding, H. et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 61, 3826–3836 (2001).

    CAS  PubMed  Google Scholar 

  108. Ding, H. et al. Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Res. 63, 1106–1113 (2003).

    CAS  PubMed  Google Scholar 

  109. Rich, J. N. et al. A genetically tractable model of human glioma formation. Cancer Res. 61, 3556–3560 (2001).

    CAS  PubMed  Google Scholar 

  110. Sonoda, Y. et al. Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res. 61, 4956–4960 (2001).

    CAS  PubMed  Google Scholar 

  111. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242–248 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Bergers, G. et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003). Elegant delineation of the relative contributions of vascular components to sustained tumour angiogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lesniak, M. S., Langer, R. & Brem, H. Drug delivery to tumors of the central nervous system. Curr. Neurol. Neurosci. Rep. 1, 210–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Pardridge, W. M. Molecular biology of the blood–brain barrier. Methods Mol. Med. 89, 385–399 (2003).

    CAS  PubMed  Google Scholar 

  115. Kenney, J. et al. Measurement of blood–brain barrier permeability in a tumor model using magnetic resonance imaging with gadolinium-DTPA. Magn. Reson. Med. 27, 68–75 (1992).

    Article  CAS  PubMed  Google Scholar 

  116. Boucher, Y. et al. Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br. J. Cancer 75, 829–836 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bendell, J. C. et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97, 2972–2977 (2003).

    Article  PubMed  Google Scholar 

  118. Reardon, D. A. et al. Phase II trial of murine (131)I-labeled anti-tenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J. Clin. Oncol. 20, 1389–1397 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Williams, J. A. et al. Preirradiation osmotic blood-brain barrier disruption plus combination chemotherapy in gliomas: quantitation of tumor response to assess chemosensitivity. Adv. Exp. Med. Biol. 331, 273–284 (1993).

    Article  CAS  PubMed  Google Scholar 

  120. Matsukado, K., Sugita, M. & Black, K. L. Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas. Brain Res. 792, 10–15 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Bobo, R. H. et al. Convection-enhanced delivery of macromolecules in the brain. Proc. Natl Acad. Sci. USA 91, 2076–2080 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Aboody, K. S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl Acad. Sci USA 97, 12846–12851 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pietras, K. et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 61, 2929–2934 (2001).

    CAS  PubMed  Google Scholar 

  124. Sampson, J. H. et al. Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-α and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J. Neurooncol. 65, 27–35 (2003).

    Article  PubMed  Google Scholar 

  125. Debinski, W. et al. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin. Clin. Cancer Res. 1, 1253–1258 (1995).

    CAS  PubMed  Google Scholar 

  126. Weber, F. et al. Safety, tolerability, and tumor response of IL4–Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J. Neurooncol. 64, 125–137 (2003).

    PubMed  Google Scholar 

  127. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001). Seminal proof of principle of clinical efficacy of small-molecule signal transduction inhibitors in cancer therapy.

    Article  CAS  PubMed  Google Scholar 

  128. Joensuu, H. et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344, 1052–1056 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Pandita, A. et al. Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR. Genes Chromosomes Cancer 39, 29–36 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Weiss, W. A. et al. Neuropathology of genetically engineered mice: consensus report and recommendations from an international forum. Oncogene 21, 7453–7463 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Gossmann, A. et al. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme. J. Magn. Reson. Imaging 15, 233–240 (2002).

    Article  PubMed  Google Scholar 

  132. Grossman, S. A. et al. Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The new approaches to brain tumor therapy. Cancer Chemother. Pharmacol. 42, 118–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. De Smet, P. Drug therapy: Herbal remedies. N. Engl. J. Med. 347, 2046–2056 (2002).

    Article  PubMed  Google Scholar 

  134. Ranson, M. et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J. Clin. Oncol. 20, 2240–2250 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Felsher, D. W. Cancer revoked: Oncogenes as therapeutic targets. Nature Rev. Cancer 3, 375–379 (2003).

    Article  CAS  Google Scholar 

  136. Wong, A. J. et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc. Natl Acad. Sci. USA 84, 6899–6903 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sugawa, N., Ekstrand, A. J., James, C. D. & Collins V. P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc. Natl Acad. Sci. USA 87, 8602–8606 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Huang, H. S. 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. 272, 2927–2935 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Lund-Johansen, M. et al. Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro. Cancer Res. 50, 6039–6044 (1990).

    CAS  PubMed  Google Scholar 

  140. Goldman, C. K. et al. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol. Biol. Cell 4, 121–133 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  143. Shinojima, N. et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 63, 6962–6970 (2003).

    CAS  PubMed  Google Scholar 

  144. Wikstrand, C. J. & Bigner, D. D. Prognostic applications of the epidermal growth factor receptor and its ligand, transforming growth factor-α. J. Natl Cancer Inst. 90, 799–801 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Miyaji, K. et al. Effect of tyrphostin on cell growth and tyrosine kinase activity of epidermal growth factor receptor in human gliomas. J. Neurosurg. 81, 411–419 (1994).

    Article  CAS  PubMed  Google Scholar 

  146. Han, Y. et al. Tyrphostin AG 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors. Cancer Res. 56, 3859–3861 (1996).

    CAS  PubMed  Google Scholar 

  147. Penar, P. L., Khoshyomn, S., Bhushan, A. & Tritton, T. R. Inhibition of epidermal growth factor receptor-associated tyrosine kinase blocks glioblastoma invasion of the brain. Neurosurgery 40, 141–151 (1997).

    CAS  PubMed  Google Scholar 

  148. Rich, J. N. et al. Phase II trial of gefitinib in recurrent glioblastoma. J. Clin. Oncol. 22, 133–142 (2004). A report on the outcome of the first completed trial of EGFR tyrosine kinase inhibitors in recurrent glioblastoma, which showed modest efficacy.

    Article  CAS  PubMed  Google Scholar 

  149. Lieberman, F. S. et al. Phase I–II study of ZD-1839 for recurrent malignant gliomas and meningiomas progressing after radiation therapy. Proc. Am. Soc. Clin. Oncol. 22, 105 (2003).

    Google Scholar 

  150. Prados, M. et al. Phase I study of OSI–774 alone or with temozolomide in patients with malignant glioma. Proc. Am. Soc. Clin. Oncol. 22, 99 (2003).

    Google Scholar 

  151. Vogelbaum, M. A. et al. Initial experience with the EGFR tyrosine kinase inhibitor Tarceva (OSI-774) for single-agent therapy of recurrent/progressive glioblastoma multiforme. Abstracts of the Society of Neuro-Oncology Eighth Annual Meeting. Neuro-oncol. 5, 356 (2003).

    Google Scholar 

  152. Mishima, K. 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. 61, 5349–5354 (2001).

    CAS  PubMed  Google Scholar 

  153. Sampson, J. H. et al. Unarmed, tumor specific monoclonal antibody effectively treats brain tumors. Proc. Natl Acad. Sci. USA 97, 7503–7508 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Grossman, S. A. et al. Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas. J. Clin. Oncol. 19, 3260–3266 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Yu, J., Ustach, C. & Kim, H. R. Platelet-derived growth factor signaling and human cancer. J. Biochem. Mol. Biol. 36, 49–59 (2003).

    CAS  PubMed  Google Scholar 

  156. Lokker, N. A., Sullivan, C. M., Hollenbach, S. J., Israel, M. A. & Giese, N. A. 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 might play a role in the development of brain tumors. Cancer Res. 62, 3729–3735 (2002).

    CAS  PubMed  Google Scholar 

  157. Uhrbom, L., Hesselager, G., Nister, M. & Westermark, B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 58, 5275–5279 (1998).

    CAS  PubMed  Google Scholar 

  158. Kilic, T. et al. Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res. 60, 5143–5150 (2000).

    CAS  PubMed  Google Scholar 

  159. Shawver, L. K. et al. Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide. Clin. Cancer Res. 3, 1167–1177 (1997).

    CAS  PubMed  Google Scholar 

  160. Vassbotn, F. S. et al. Activated platelet-derived growth factor autocrine pathway drives the transformed phenotype of a human glioblastoma cell line. J. Cell. Physiol. 158, 381–389 (1994).

    Article  CAS  PubMed  Google Scholar 

  161. Strawn, L. M. et al. Inhibition of glioma cell growth by a truncated platelet-derived growth factor-β receptor. J. Biol. Chem. 269, 21215–21222 (1994).

    Article  CAS  PubMed  Google Scholar 

  162. Behl, C. et al. Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules. Neurosurgery 33, 679–684 (1993).

    CAS  PubMed  Google Scholar 

  163. Shamah, S. M., Stiles, C. D. & Guha, A. Dominant-negative mutants of platelet-derived growth factor revert the transformed phenotype of human astrocytoma cells. Mol. Cell. Biol. 13, 7203–7212 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Wen, P. Y. et al. Phase I study of STI571 (Gleevec) for patients with recurrent malignant gliomas and meningiomas (NABTC 99–08). Proc. Am. Soc. Clin. Oncol. 21, 73A (2002).

    Google Scholar 

  165. Dresemann, G. STI 571/hydroxyurea in progressive, pretreated glioblastoma (GB) patients (pts.). Proc. Am. Soc. Clin. Oncol. 22, 116 (2003).

    Google Scholar 

  166. Fong, T. A. et al. 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 (1999).

    CAS  PubMed  Google Scholar 

  167. Laird, A. D. et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4160 (2000).

    CAS  PubMed  Google Scholar 

  168. Yung, W. K. A. et al. A phase I trial of single-agent PTK 787/ZK 222584 (PTK/ZK), an oral VEGFR tyrosine kinase inhibitor, in patients with recurrent glioblastoma multiforme. Proc. Am. Soc. Clin. Oncol. 22, 99 (2003).

    Google Scholar 

  169. Reardon, D et al. Preliminary phase I trial results: PTK787/ZK222584 (PTK/ZK), an oral VEGF tyrosine kinase inhibitor, in combination with either temozolomide or lomustine for patients with recurrent glioblastoma multiforme. Abstracts of the Society of Neuro-Oncology Eighth Annual Meeting. Neuro-oncol. 5, 355 (2003).

    Google Scholar 

  170. Sebti, S. M. & Der, C. J. Searching for the elusive targets of farnesyltransferase inhibitors. Nature Rev. Cancer 3, 945–951 (2003).

    Article  CAS  Google Scholar 

  171. Kohl, N. E. et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260, 1934–1937 (1993).

    Article  CAS  PubMed  Google Scholar 

  172. Bredel, M., Pollack, I. F., Freund, J. M., Hamilton, A. D. & Sebti, S. M. Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth. Neurosurgery 43, 124–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  173. Cloughesy, T. F. et al. Phase II trial of R115777 (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. 21, 80A (2002).

    Google Scholar 

  174. Kuhn, J. G. et al. Phase I trial of R115777 (Zarnestra) in patients with recurrent malignant glioma taking enzyme inducting antiepileptic drugs (EIAED). A North American Brain Tumor Consortium (NABTC) report. Proc. Am. Soc. Clin. Oncol. 21, 86A (2002).

    Google Scholar 

  175. Shamji, A. F., Nghiem, P. & Schreiber, S. L. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol. Cell 12, 271–280 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Abraham, R. T. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 111, 9–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. Singh, K., Sun, S. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action. J. Antibiot. (Tokyo) 32, 630–645 (1979).

    Article  CAS  Google Scholar 

  178. Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell. Biol. 22, 7004–7014 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Houchens, D. P., Ovejera, A. A., Riblet, S. M. & Slagel, D. E. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur. J. Cancer Clin. Oncol. 19, 799–805 (1983).

    Article  CAS  PubMed  Google Scholar 

  180. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001). An important indicator of a molecular predictor of a targeted therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chang, S. et al. Phase II/pharmacokinetic study of CCI-779 in recurrent glioblastoma multiforme. Abstracts of the Society of Neuro-Oncology Eighth Annual Meeting. Neuro-oncol. 5, 349 (2003).

    Google Scholar 

  182. Rich, J. N. The role of transforming growth factor-β in primary brain tumors. Front. Biosci. 8, E245–E260 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Fakhrai, H. et al. Eradication of established intracranial rat gliomas by transforming growth factor β antisense gene therapy. Proc. Natl Acad. Sci. USA 93, 2909–2914 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Stauder, G. M. et al. A TGF-β2 specific antisense oligonucleotide (AP12009) as continuous intratumoral treatment of recurrent high-grade glioma patients: A clinical phase I/II extension study. Proc. Am. Soc. Clin. Oncol. 22, 109 (2003).

    Google Scholar 

  185. Rich, J. N., Zhang, M., Datto, M. B., Bigner, D. D. & Wang, X. F. Transforming growth factor-β-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J. Biol. Chem. 274, 35053–35058 (1999).

    Article  CAS  PubMed  Google Scholar 

  186. Hjelmeland, M. D. et al. SB431542, a small molecule transforming growth factor-α-receptor antagonist, inhibits human glioma xenograft malignant phenotype. 2003 AACR-NCI–EORTC Int. Conf. Molecular Targets Cancer Therapeutics A C136 (2003).

  187. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  188. Li, B. et al. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res. 63, 7443–7450 (2003).

    CAS  PubMed  Google Scholar 

  189. Chakravarti, A., Loeffler, J. S. & Dyson, N. J. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 62, 200–207 (2002).

    CAS  PubMed  Google Scholar 

  190. Klingler-Hoffmann, M., Bukczynska, P. & Tiganis, T. Inhibition of phosphatidylinositol 3-kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells. Int. J. Cancer 105, 331–339 (2003).

    Article  CAS  PubMed  Google Scholar 

  191. Baker, C. H., Solorzano, C. C. & Fidler, I. J. Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res. 62, 1996–2003 (2002).

    CAS  PubMed  Google Scholar 

  192. Goudar, R. et al. Combination therapy of inhibitors of the epidermal growth factor/ vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. 2003 AACR-NCI–EORTC Int. Conf. Molecular Targets Cancer Therapeutics A A88 (2003).

  193. Rao, R. D. et al. Synergistic inhibition of glioma cell growth upon combination therapy with the mTOR inhibitor, rapamycin, and the epidermal growth factor receptor inhibitor, EKI-785. Proc. Am. Assoc. Cancer Res. 44, A718 (2003).

    Google Scholar 

  194. Nagane, M. et al. Human glioblastoma xenografts overexpressing a tumor-specific mutant epidermal growth factor receptor sensitized to cisplatin by the AG1478 tyrosine kinase inhibitor. J. Neurosurg. 95, 472–479 (2001).

    Article  CAS  PubMed  Google Scholar 

  195. Chakravarti, A. et al. The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Res. 62, 4307–4315 (2002).

    CAS  PubMed  Google Scholar 

  196. Geng, L. et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 61, 2413–2419 (2001).

    CAS  PubMed  Google Scholar 

  197. Giaccone, G. et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a Phase III trial — INTACT 1. J. Clin. Oncol. 22, 777–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  198. Herbst, R. S. et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a Phase III trial — INTACT 2. J. Clin. Oncol. 22, 785–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  199. Tremont-Lukats, I. W. & Gilbert, M. R. Advances in molecular therapies in patients with brain tumors. Cancer Control 10, 125–137 (2003).

    Article  PubMed  Google Scholar 

  200. Rao, R. D., Uhm, J. H., Krishnan, S. & James, C. D. Genetic and signaling pathway alterations in glioblastoma: relevance to novel targeted therapies. Front. Biosci. 8, E270–E280 (2003).

    Article  CAS  PubMed  Google Scholar 

  201. Mischel, P. S. & Cloughesy, T. F. Targeted molecular therapy of GBM. Brain Pathol. 13, 52–61 (2003).

    Article  PubMed  Google Scholar 

  202. Newton, H. B. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways. Expert Rev. Anticancer Ther. 3, 595–614 (2003).

    Article  CAS  PubMed  Google Scholar 

  203. Reilly, K. M. & Jacks, T. Genetically engineered mouse models of astrocytoma: GEMs in the rough? Semin. Cancer Biol. 11, 177–191 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank H. Friedman, J. Quinn, C. Wikstrand, X.-F. Wang, D. Reardon, J. Vredenburgh, R. McLendon and T. Curran for helpful discussions. This work was supported in part by funding from the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure and the Southeastern Brain Tumor Foundation. This work was supported by National Institutes of Health grants, General Clinical Research Center Program, National Center for Research Resources, a National Cancer Institute grant, Finding Cures for Glioblastoma grants, and a grant from the Pediatric Brain Tumor Foundation of the United States.

Author information

Authors and Affiliations

  1. Departments of Medicine and Neurobiology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Jeremy N. Rich

  2. Department of Pathology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Darell D. Bigner

Authors
  1. Jeremy N. Rich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Darell D. Bigner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy N. Rich.

Ethics declarations

Competing interests

J. R. has seved as a paid consultant for Novartis.

Related links

Related links

DATABASES

LocusLink

4E-BP1

BAX

CDK4

EGF

FKBP12

HDM2

HGF/SF

IGF1

IL-13

IL-4

mTOR

p15INK4B

p16INK4A

p70S6K

PDGF

PTEN

SMAC

TGF-α

TGF-β

TP53

TRAIL

VEGF

Glossary

TUMOUR XENOGRAFT

Tumour specimens can be grown in immunocompromised rodents to provide tumour models with many of the complexities of human tumours.

CLINICAL ENDPOINT

A characteristic or variable that reflects how a patient feels or functions, or how long a patient survives.

BIOMARKER

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rich, J., Bigner, D. Development of novel targeted therapies in the treatment of malignant glioma. Nat Rev Drug Discov 3, 430–446 (2004). https://doi.org/10.1038/nrd1380

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1380

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing