Skip to main content

Advertisement

SpringerLink
Log in

Antiangiogenic therapy in the management of brain tumors: a clinical overview

  • Review Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Central to the process of brain tumor development is angiogenesis, which involves a host of molecules and receptors. In recent years, antiangiogenic therapies have been developed and tested for their effectiveness against these tumors. Among them are inhibitors against vascular endothelial growth factor and its receptors, as well as inhibitors targeting the platelet-derived growth factor family, integrins, and histone deacetylase. While many have been shown to be effective with limited toxicity, some tumors are able to adopt escape mechanisms. Further research is needed in the development of effective multi-targeted agents to reduce these effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fidler IJ (1999) Critical determinants of cancer metastasis: rationale for therapy. Cancer Chemother Pharmaco 43:S3–S10

    Article  CAS  Google Scholar 

  2. Jiménez B, Volpert OV (2001) Mechanistic insights on the inhibition of tumor angiogenesis. J Mol Med 78(12):663–672

    Article  PubMed  Google Scholar 

  3. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027

    Article  PubMed  CAS  Google Scholar 

  4. Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10):2003–2012

    Article  PubMed  CAS  Google Scholar 

  5. Bautch VL, Redick SD, Scalia A, Harmaty M, Carmeliet P, Rapoport R (2000) Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A. Blood 95(6):1979–1987

    PubMed  CAS  Google Scholar 

  6. Fong G-H, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535):66–70

    Article  PubMed  CAS  Google Scholar 

  7. Shalaby F, Rossant J, Yamaguchi TP et al (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376(6535):62–66

    Article  PubMed  CAS  Google Scholar 

  8. Zagzag D, Amirnovin R, Greco MA et al (2000) Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80(6):837–849

    Article  PubMed  CAS  Google Scholar 

  9. Zagzag D, Lukyanov Y, Lan L et al (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86(12):1221–1232

    Article  PubMed  CAS  Google Scholar 

  10. Vredenburgh J, Desjardins A, Herndon J et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729

    Article  PubMed  CAS  Google Scholar 

  11. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740

    Article  PubMed  CAS  Google Scholar 

  12. Nghiemphu PL, Liu W et al (2009) Bevacizumab and chemotherapy for recurrent glioblastoma. Neurology 72(14):1217–1222

    Article  PubMed  CAS  Google Scholar 

  13. Kerber M, Reiss Y et al (2008) Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res 68(18):7342–7351

    Article  PubMed  CAS  Google Scholar 

  14. Geng L, Donnelly E et al (2001) Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 61(6):2413–2419

    PubMed  CAS  Google Scholar 

  15. Pietsch T, Valter MM, Wolf HK et al (1997) Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol 93(2):109–117

    Article  PubMed  CAS  Google Scholar 

  16. Caye-Thomasen P et al (2005) VEGF and VEGF receptor-1 concentration in vestibular schwannoma homogenates correlates to tumor growth rate. [Miscellaneous Article]. Otol Neurotol 26(1):98–101

    Article  PubMed  Google Scholar 

  17. Hoch RV, Soriano P (2003) Roles of PDGF in animal development. Development 130(20):4769–4784

    Article  PubMed  CAS  Google Scholar 

  18. Andrae J, Gallini R et al (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312

    Article  PubMed  CAS  Google Scholar 

  19. Charles N, Ozawa T et al (2010) Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6(2):141–152

    Article  PubMed  CAS  Google Scholar 

  20. Lokker NA, Sullivan CM et al (2002) Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells. Cancer Res 62(13):3729–3735

    PubMed  CAS  Google Scholar 

  21. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110(6):673–687

    Article  PubMed  CAS  Google Scholar 

  22. Zhong J, Paul A et al (2010) Mesenchymal migration as a therapeutic target in glioblastoma. J Oncol 2010(21):430142

    PubMed  Google Scholar 

  23. Kanamori M, Kawaguchi T et al (2006) Intracranial microenvironment reveals independent opposing functions of host αVβ3 expression on glioma growth and angiogenesis. J Biol Chem 281(48):37256–37264

    Article  PubMed  CAS  Google Scholar 

  24. Schnell O, Krebs B et al (2008) Expression of integrin αvβ3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Patho 18(3):378–386

    Article  CAS  Google Scholar 

  25. Puduvalli V (2001) Brain metastases: biology and the role of the brain microenvironment. Curr Oncol Rep 3(6):467–475

    Article  PubMed  CAS  Google Scholar 

  26. Weber GF, Ashkar S (2000) Molecular mechanisms of tumor dissemination in primary and metastatic brain cancers. Brain Res Bull 53(4):421–424

    Article  PubMed  CAS  Google Scholar 

  27. Ouaissi M, Ouaissi A (2006) Histone deacetylase enzymes as potential drug targets in cancer and parasitic diseases. J Biomed Biotechnol 2006:13474

  28. Campos B, Bermejo JL et al (2011) Expression of nuclear receptor corepressors and class I histone deacetylases in astrocytic gliomas. Cancer Sci 102(2):387–392

    Article  PubMed  CAS  Google Scholar 

  29. Sharma V, Koul N et al (2010) HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J Cell Mol Med 14(8):2151–2161

    Article  PubMed  CAS  Google Scholar 

  30. Thudi NK, Shu ST et al (2011) Development of a brain metastatic canine prostate cancer cell line. Prostate 71(12):1251–1263

    PubMed  CAS  Google Scholar 

  31. Vredenburgh JJ, Desjardins A et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259

    Article  PubMed  CAS  Google Scholar 

  32. Kreisl TN, Kim L et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745

    Article  PubMed  CAS  Google Scholar 

  33. Narayana A, Kelly P et al (2009) Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurgery 110(1):173–180

    Article  Google Scholar 

  34. Norden AD, Young GS et al (2008) Bevacizumab for recurrent malignant gliomas. Neurology 70(10):779–787

    Article  PubMed  CAS  Google Scholar 

  35. Lai A, Tran A et al (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29(2):142–148

    Article  PubMed  CAS  Google Scholar 

  36. Narayana A, Golfinos JG et al (2008) Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. Int J Rad Oncol Biol Phys 72(2):383–389

    Article  CAS  Google Scholar 

  37. Vredenburgh JJ, Desjardins A et al (2012) Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme. Int J Rad Oncol Biol Phys 82(1):58–66

    Article  CAS  Google Scholar 

  38. Narayana A, Gruber D et al (2012) A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurgery 116(2):341–345

    Article  CAS  Google Scholar 

  39. Chamberlain MC, Johnston S (2009) Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer 115(8):1734–1743

    Article  PubMed  CAS  Google Scholar 

  40. Mautner V-F, Nguyen R et al (2010) Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro-Oncol 12(1):14–18

    Article  PubMed  Google Scholar 

  41. Plotkin SR, Stemmer-Rachamimov AO et al (2009) Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361(4):358–367

    Article  PubMed  CAS  Google Scholar 

  42. Mautner V-F, Nguyen R et al (2010) Radiographic regression of vestibular schwannomas induced by bevacizumab treatment: sustain under continuous drug application and rebound after drug discontinuation. Ann Oncol 21(11):2294–2295

    Article  PubMed  Google Scholar 

  43. Puchner MJA, Hans VH et al (2010) Bevacizumab-induced regression of anaplastic meningioma. Ann Oncol 21(12):2445–2446

    Article  PubMed  CAS  Google Scholar 

  44. Goutagny S, Raymond E et al (2011) Radiographic regression of cranial meningioma in a NF2 patient treated by bevacizumab. Ann Oncol 22(4):990–991

    Article  PubMed  CAS  Google Scholar 

  45. Socinski MA, Langer CJ et al (2009) Safety of bevacizumab in patients with non–small-cell lung cancer and brain metastases. J Clin Oncol 27(31):5255–5261

    Article  PubMed  CAS  Google Scholar 

  46. Labidi SI, Bachelot T et al (2009) Bevacizumab and paclitaxel for breast cancer patients with central nervous system metastases: a case series. Clin Breast Cancer 9(2):118–121

    Article  PubMed  CAS  Google Scholar 

  47. Wong ET, Huberman M et al (2008) Bevacizumab reverses cerebral radiation necrosis. J Clin Oncol 26(34):5649–5650

    Article  PubMed  Google Scholar 

  48. Torcuator R, Zuniga R et al (2009) Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neuro-Oncol 94(1):63–68

    Article  CAS  Google Scholar 

  49. Spratlin JL, Mulder KE et al (2010) Ramucirumab (IMC-1121B): a novel attack on angiogenesis. Fut Oncol 6(7):1085–1094

    Article  CAS  Google Scholar 

  50. Spratlin JL, Cohen RB et al (2010) Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 28(5):780–787

    Article  PubMed  CAS  Google Scholar 

  51. Farrar CT, Kamoun WS et al (2011) Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model. PLoS One 6(3):e17228

    Article  PubMed  CAS  Google Scholar 

  52. Dietrich J, Wang D et al (2009) Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma. Expert Opin Investig Drugs 18(10):1549–1557

    Article  PubMed  CAS  Google Scholar 

  53. Batchelor TT, Duda DG et al (2010) Phase II study of cediranib, an oral pan–vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28(17):2817–2823

    Article  PubMed  CAS  Google Scholar 

  54. Wachsberger PR, Lawrence YR et al (2012) Epidermal growth factor receptor expression modulates antitumor efficacy of vandetanib or cediranib combined with radiotherapy in human glioblastoma xenografts. Int J Rad Oncol Biol Phys 82(1):483–491

    Article  CAS  Google Scholar 

  55. Siegelin MD, Raskett CM et al (2010) Sorafenib exerts anti-glioma activity in vitro and in vivo. Neurosci Lett 478(3):165–170

    Article  PubMed  CAS  Google Scholar 

  56. Navis AC, Hamans BC et al (2011) Effects of targeting the VEGF and PDGF pathways in diffuse orthotopic glioma models. The J Pathol 223(5):626–634

    Article  Google Scholar 

  57. Neyns B, Sadones J et al (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neuro-Oncol 103(3):491–501

    Article  CAS  Google Scholar 

  58. Hainsworth JD, Ervin T et al (2010) Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer 116(15):3663–3669

    Article  PubMed  CAS  Google Scholar 

  59. Yoshikawa A, Nakada M et al (2012) Recurrent anaplastic meningioma treated by sunitinib based on results from quantitative proteomics. Neuropathol Appl Neurobiol 38(1):105–110

    Article  PubMed  CAS  Google Scholar 

  60. Amaravadi RK, Schuchter LM et al (2009) Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases. Clin Cancer Res 15(24):7711–7718

    Article  PubMed  CAS  Google Scholar 

  61. Gore ME, Hariharan S et al (2011) Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer 117(3):501–509

    Article  PubMed  CAS  Google Scholar 

  62. Wuthrick EJ, Kamrava M et al (2011) A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies. Cancer 117(24):5548–5559

    Article  PubMed  CAS  Google Scholar 

  63. Maurer GD, Tritschler I et al (2009) Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro. Neuro-Oncol 11(6):747–756

    Article  PubMed  CAS  Google Scholar 

  64. Reardon DA, Fink KL et al (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26(34):5610–5617

    Article  PubMed  CAS  Google Scholar 

  65. Stupp R, Hegi ME et al (2010) Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28(16):2712–2718

    Article  PubMed  CAS  Google Scholar 

  66. Sawa H, Murakami H et al (2004) Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo. Acta Neuropathol 107(6):523–531

    Article  PubMed  CAS  Google Scholar 

  67. Iwamoto FM, Lamborn KR et al (2011) A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American brain tumor consortium study 03–03. Neuro-Oncol 13(5):509–516

    Article  PubMed  CAS  Google Scholar 

  68. Berg SL, Stone J et al (2004) Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother Pharmacol 54(1):85–88

    Article  PubMed  CAS  Google Scholar 

  69. Hariharan S, Gustafson D et al (2007) Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol 18(8):1400–1407

    Article  PubMed  CAS  Google Scholar 

  70. Shah MH, Binkley P et al (2006) Cardio toxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 12(13):3997–4003

    Article  PubMed  CAS  Google Scholar 

  71. Rini BI, Choueiri TK et al (2008) Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma. Cancer 113(6):1309–1314

    Article  PubMed  CAS  Google Scholar 

  72. Brunello A, Saia G et al (2009) Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44(1):173–175

    Article  PubMed  CAS  Google Scholar 

  73. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603

    Article  PubMed  CAS  Google Scholar 

  74. Lucio-Eterovic AK, Piao Y et al (2009) Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res 15(14):4589–4599

    Article  PubMed  CAS  Google Scholar 

  75. de Groot JF, Fuller G et al (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro-Oncol 12(3):233–242

    Article  PubMed  Google Scholar 

  76. Iwamoto FM, Abrey LE et al (2009) Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73(15):1200–1206

    Article  PubMed  CAS  Google Scholar 

  77. Narayana A, Kunnakkat SD et al (2012) Change in pattern of relapse after antiangiogenic therapy in high-grade glioma. Int J Rad Oncol Biol Phys 82(1):77–82

    Article  Google Scholar 

  78. Wen PY, Macdonald DR et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, New York University Langone Medical Center, 550 1st Ave., New York, NY, 10016, USA

    Saroj Kunnakkat, Maya Mathew & Ashwatha Narayana

Authors
  1. Saroj Kunnakkat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maya Mathew
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashwatha Narayana
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashwatha Narayana.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kunnakkat, S., Mathew, M. & Narayana, A. Antiangiogenic therapy in the management of brain tumors: a clinical overview. Cancer Chemother Pharmacol 70, 353–363 (2012). https://doi.org/10.1007/s00280-012-1926-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-1926-7

Keywords

Search

Navigation