Antiangiogenesis Treatment for Glioblastoma Multiforme: Challenges and Opportunities

Authors: Eric T. Wong MD a and Steven Brem MD a
View More View Less
  • a From Brain Tumor Center & Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, and Department of Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida College of Medicine, Tampa, Florida.

Angiogenesis is a major hallmark of cancer cells, and glioblastomas are among the most angiogenic tumors. The cascade of angiogenesis is probably initiated by hypoxia, leading to the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Both VEGF and bFGF have paracrine effects on endothelial cells, pericytes, or both, causing the formation of hyperpermeable tumor blood vessels. Advanced MRI techniques, such as dynamic contrast-enhanced, dynamic susceptibility, and arterial spin labeling MRI, have provided semiquantitative measurements of tumor vascular permeability and perfusion. A decrease in vascular permeability and perfusion can be detected after antiangiogenesis drug treatment, either with monoclonal antibody such as bevacizumab that sequesters VEGF, or small-molecule VEGF receptor tyrosine kinase inhibitors. Therefore, antiangiogenesis therapies are being increasingly adopted for treating glioblastomas. However, caution must be exercised because neural stem cells are also sensitive to antiangiogenesis drugs and the combined effect of ionizing radiation. This article summarizes 30 years of laboratory and clinical research on glioblastoma angiogenesis and discusses its underlying biology, clinical trial results, vascular neuroimaging, and the potential side effects of antiangiogenesis treatment.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Eric T. Wong, MD, Brain Tumor Center & Neuro-Oncology Unit, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: ewong@bidmc.harvard.edu
  • 1.

    Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitative method of histological grading. J Natl Cancer Inst 1972;48:347356.

  • 2.

    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:11821186.

  • 3.

    Willett CG, Boucher Y, di Tomaso E. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145147.

    • Search Google Scholar
    • Export Citation
  • 4.

    Willett CG, Boucher Y, di Tomaso E. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:649.

    • Search Google Scholar
    • Export Citation
  • 5.

    Mayer RJ. Two steps forward in the treatment of colorectal cancer. New Engl J Med 2004;350:24062408.

  • 6.

    Shweiki D, Itin A, Soffer D. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843845.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lal A, Peters H, St. Croix B. Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 2001;93:13371343.

  • 8.

    Maxwell P, Dachs G, Gleadle J. Hypoxia-inducible factor-1 modulates gene expression in solid tumorsand influences both angiogenesis and tumor growth. Proc Natl Acad Sci 1997;94:81048109.

    • Search Google Scholar
    • Export Citation
  • 9.

    Maxwell P, Weisner M, Chang GW. The tumor suppressor protein VHL targets hypoxia-induced factors for oxygen dependent proteolysis. Nature 1999;399:271275.

    • Search Google Scholar
    • Export Citation
  • 10.

    Kondo K, Klco J, Nakamura E. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237246.

    • Search Google Scholar
    • Export Citation
  • 11.

    Tanimoto K, Makino Y, Pereira T. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J 2000;19:42984309.

    • Search Google Scholar
    • Export Citation
  • 12.

    Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol 2004;22:49915004.

  • 13.

    Lonser RR, Kim HJ, Butman JA. Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med 2004;350:24812486.

  • 14.

    Plate KH, Breier G, Weich HA. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992;359:845848.

    • Search Google Scholar
    • Export Citation
  • 15.

    Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:10111027.

    • Search Google Scholar
    • Export Citation
  • 16.

    Joensuu H, Puputti M, Sihto H. Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol 2005;207:224231.

    • Search Google Scholar
    • Export Citation
  • 17.

    Gampel A, Moss L, Jones MC. VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. Blood 2006;108:26242631.

    • Search Google Scholar
    • Export Citation
  • 18.

    Bergers G, Brekken R, McMahon G. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000;2:737744.

    • Search Google Scholar
    • Export Citation
  • 19.

    Coussens LM, Tinkle CL, Hanahan D. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 2000;103:481490.

  • 20.

    Lyden D, Hattori K, Dias S. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001;7:11941201.

    • Search Google Scholar
    • Export Citation
  • 21.

    Mancuso P, Burlini A, Pruneri G. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 2001;97:36583661.

    • Search Google Scholar
    • Export Citation
  • 22.

    Pezzolo A, Parodi F, Corria MV. Tumor origin of endothelial cells in human neuroblastoma. J Clin Oncol 2007;25:376383.

  • 23.

    Zagzag D, Miller DC, Sato Y. Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res 1990;50:73937398.

    • Search Google Scholar
    • Export Citation
  • 24.

    Morrison RS, Yamaguchi F, Bruner JM. Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Cancer Res 1994;54:27942799.

    • Search Google Scholar
    • Export Citation
  • 25.

    Kano MR, Morishita Y, Iwata C. VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogeneous PDGF-B-PDGFRβ signaling. J Cell Sci 2005;118:37593768.

    • Search Google Scholar
    • Export Citation
  • 26.

    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987989.

  • 27.

    Vredenburg JJ, Desjardins A, Herndon JE. Bevacizumab and irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:47224729.

  • 28.

    Hasselbalch B, Lassen U, Grunnet K. Bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), and irinotecan for treatment of recurrent primary malignant brain tumors in adults. Neuro-Oncology 2007;9:514515.

    • Search Google Scholar
    • Export Citation
  • 29.

    Wong ET, Hess KR, Gleason MJ. Outcomes and prognostic factors in recurrent glioma patients enrolled in phase II clinical trials. J Clin Oncol 1999;17:25722578.

    • Search Google Scholar
    • Export Citation
  • 30.

    Sathornsumetee S, Cao Y, Marcello JE. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 2008;26:271278.

    • Search Google Scholar
    • Export Citation
  • 31.

    Calabrese C, Poppleton H, Kocak M. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11:6982.

  • 32.

    Gilbertson RJ, Rich JN. Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 2007;733736.

  • 33.

    Sakarassen , Prestegarden L, Wang J. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA 2006;103;1646616471.

    • Search Google Scholar
    • Export Citation
  • 34.

    Winkler F, Kozin SV, Tong RT. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6:553563.

    • Search Google Scholar
    • Export Citation
  • 35.

    Batchelor TT, Sorensen AG, di Tomaso E. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:8395.

    • Search Google Scholar
    • Export Citation
  • 36.

    Man S, Bocci G, Francia G. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 2002;62:27312735.

    • Search Google Scholar
    • Export Citation
  • 37.

    Emmenegger U, Man S, Shaked Y. A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maxium tolerated dose regimens. Cancer Res 2004;64:39944000.

    • Search Google Scholar
    • Export Citation
  • 38.

    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423436.

  • 39.

    Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet 2001;2:733740.

  • 40.

    Bocci G, Francia G, Man S. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 2003;100:1291712922.

    • Search Google Scholar
    • Export Citation
  • 41.

    Bertolini F, Paul S, Mancuso P. Maximum tolerated dose and low-dose metronomic chemotherapy have opposite effects on mobilization and viability of circulating endothelial progenitor cells. Cancer Res 2003;63:43424346.

    • Search Google Scholar
    • Export Citation
  • 42.

    Herrlinger U, Rieger J, Steinbach JP. UKT-04 trial of continuous metronomic low-dose chemotherapy with methotrexate and cyclophosphamide for recurrent glioblastoma. J Neurooncol 2005;71:295299.

    • Search Google Scholar
    • Export Citation
  • 43.

    Kim JT, Kim JS, Ko KW. Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep 2006;16:3339.

    • Search Google Scholar
    • Export Citation
  • 44.

    Østergaard L. Principles of cerebral perfusion imaging by bolus tracking. J Mag Reson Imaging 2005;22:710717.

  • 45.

    Wong ET, Jackson EF, Hess KR. Correlation between dynamic MRI and outcome in patients with malignant gliomas. Neurology 1998;50:777781.

  • 46.

    Roberts HC, Roberts TPL, Brasch RC. Quantitative measurements of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR Imaging: correlation with histologic grade. AJNR Am J Neuroradiol 2000;21:891899.

    • Search Google Scholar
    • Export Citation
  • 47.

    Wilmes LJ, Pallavicini MG, Fleming LM. AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Mag Reson Imaging 2007;25:319327.

    • Search Google Scholar
    • Export Citation
  • 48.

    Williams DS, Detre JA, Leigh JS. Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci USA 1992;89:212216.

    • Search Google Scholar
    • Export Citation
  • 49.

    Walsh EG, Minematsu K, Leppo J. Radioactive microsphere validation of a volume localized continuous saturation perfusion measurement. Magn Reson Med 1994;31:147153.

    • Search Google Scholar
    • Export Citation
  • 50.

    Ye FQ, Berman KF, Ellmore T. H 15 2O PET validation of Steady-state arterial spin tagging cerebral blood flow measurements in humans. Magn Reson Med 2000;44:450456.

    • Search Google Scholar
    • Export Citation
  • 51.

    Chalela JA, Alsop DC, Gonzalez-Atavales JB. Magnetic resonance perfusion imaging in acute ischemic stroke using continuous arterial spin labeling. Stroke 2000;31:680687.

    • Search Google Scholar
    • Export Citation
  • 52.

    Detre JA, Alsop DC, Vives LR. Noninvasive MRI evaluation of cerebral blood flow in cerebrovascular disease. Neurology 1998;50:633641.

  • 53.

    Detre JA, Samuels OB, Alsop DC. Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis. J Magn Reson Imaging 1999;10:870875.

    • Search Google Scholar
    • Export Citation
  • 54.

    Wolf RL, Alsop DC, Levy-Reis I. Detection of mesial temporal lobe hypoperfusion in patients with temporal lobe epilepsy using arterial spin labeled perfusion MRI. AJNR Am J Neuroradiol 2001;22:13341341.

    • Search Google Scholar
    • Export Citation
  • 55.

    Alsop DC, Detre JA, Grossman M. Assessment of cerebral blood flow in Alzheimer's disease by spin-labeled magnetic resonance imaging. Ann Neurol 2000;47:93100.

    • Search Google Scholar
    • Export Citation
  • 56.

    Warmuth C, Gunther M, Zimmer C. Quantification of blood flow in brain tumors: comparison of arterial spin labeling and dynamic susceptibility-weighted contrast-enhanced MR imaging. Radiology 2003;228:523532.

    • Search Google Scholar
    • Export Citation
  • 57.

    Weber MA, Thilmann C, Lichy MP. Assessment of irradiated brain metastases by means of arterial spin-labeling and dynamic susceptibility-weighted contrast-enhanced perfusion MRI: initial results. Invest Radiol 2004;39:277287.

    • Search Google Scholar
    • Export Citation
  • 58.

    Ye FQ, Frank JA, Weinberger DR. Noise reduction in 3D perfusion imaging by attenuating the static signal in arterial spin tagging (ASSIST). Magn Reson Med 2000;44:92100.

    • Search Google Scholar
    • Export Citation
  • 59.

    Alsop DC, Detre JA. Background suppressed 3D RARE ASL perfusion imaging. Presented at: International Society for Magnetic Resonance in Medicine Seventh Scientific Meeting and Exhibition; May 22–29, 1999; Philadelphia, PA.

    • Search Google Scholar
    • Export Citation
  • 60.

    Wang J, Alsop DC, Lin L. Comparison of quantitative perfusion imaging using arterial spin labeling at 1.5 and 4.0 Tesla. Mag Reson Med 2002;48:242254.

    • Search Google Scholar
    • Export Citation
  • 61.

    Macdonald DR, Casino TL, Schold SC Jr. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:12771280.

    • Search Google Scholar
    • Export Citation
  • 62.

    Chen W, Cloughesy T, Kamdar N. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 2005;46:945952.

  • 63.

    Miwa K, Shinoda J, Yano H. Discrepancy between lesion distributions on methionine PET and MR images in patients with glioblastoma multiforme: insight from a PET and MR fusion image study. J Neurol Neurosurg Psychiatry 2004;75:14571462.

    • Search Google Scholar
    • Export Citation
  • 64.

    Olivero WC, Dulebohn SC, Lister JR. The use of PET in evaluating patients with primary brain tumours: is it useful? J Neurol Neurosurg Psychiatry 1995;58:250252.

    • Search Google Scholar
    • Export Citation
  • 65.

    Chen W, Delaloye S, Silverman DHS. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 2007;25:47144721.

    • Search Google Scholar
    • Export Citation
  • 66.

    Vredenburgh JJ, Desjardins A, Herndon JE. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:12531259.

    • Search Google Scholar
    • Export Citation
  • 67.

    Norden AD, Young GS, Setayesh K. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and pattern of recurrence. Neurology 2008;70:779787.

    • Search Google Scholar
    • Export Citation
  • 68.

    Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with gliomas. Ann Neurol 1983;13:334336.

  • 69.

    Quevedo JF, Buckner JC, Schmidt JL. Thromboembolism in patients with high-grade glioma. Mayo Clin Proc 1994;69:329332.

  • 70.

    Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. New Engl J Med 2006;354:980982.

  • 71.

    Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch Neurol 2006;63:14751478.

    • Search Google Scholar
    • Export Citation
  • 72.

    Quinones-Hinojosa A, Sanai N, Soriano-Navarro M. Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 2006;494:415434.

    • Search Google Scholar
    • Export Citation
  • 73.

    Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000;425:479494.

  • 74.

    Li Q, Ford MC, Lavik EB. Modeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells: an in vitro study. J Neurosci Res 2006;84:16561668.

    • Search Google Scholar
    • Export Citation
  • 75.

    Narayana A, Golfinos J, Knopp E. Feasibility of using bevacizumab with radiation therapy in high grade gliomas. Int J Radiat Oncol Biol Phys 2007;69:S51.

    • Search Google Scholar
    • Export Citation
  • 76.

    Kanzawa T, Iwado E, Aoki H. Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway. Oncogene 2006;25:36383648.

    • Search Google Scholar
    • Export Citation
  • 77.

    Otsuka S, Coderre JA, Micca PL. Depletion of neural precursor cells after local brain irradiation is due to radiation dose to the parenchyma, not the vasculature. Radiat Res 2006;165:582591.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 197 75 15
PDF Downloads 110 59 3
EPUB Downloads 0 0 0