A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma

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Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Correspondence: David A. Reardon, MD, The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Box 3624, Durham, NC 27710. E-mail: reard003@mc.duke.edu
  • 1.

    StuppRMasonWPvan den BentMJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med2005;352:987996.

  • 2.

    BallmanKVBucknerJCBrownPD. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncol2007;9:2938.

    • Search Google Scholar
    • Export Citation
  • 3.

    LambornKRYungWKChangSM. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol2008;10:162170.

    • Search Google Scholar
    • Export Citation
  • 4.

    WongETHessKRGleasonMJ. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol1999;17:25722578.

    • Search Google Scholar
    • Export Citation
  • 5.

    ReardonDARichJNFriedmanHS. Recent advances in the treatment of malignant astrocytoma. J Clin Oncol2006;24:12531265.

  • 6.

    WenPYKesariS. Malignant gliomas in adults. N Engl J Med2008;359:492507.

  • 7.

    FerraraNHillanKJGerberHP. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov2004;3:391400.

    • Search Google Scholar
    • Export Citation
  • 8.

    FriedmanHSPradosMDWenPY. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol2009;27:47334740.

    • Search Google Scholar
    • Export Citation
  • 9.

    KreislTNKimLMooreK. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol2009;27:740745.

    • Search Google Scholar
    • Export Citation
  • 10.

    VredenburghJJDesjardinsAHerndonJEII. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res2007;13:12531259.

    • Search Google Scholar
    • Export Citation
  • 11.

    VredenburghJJDesjardinsAHerndonJEII. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol2007;25:47224729.

    • Search Google Scholar
    • Export Citation
  • 12.

    BremSCotranRFolkmanJ. Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst1972;48:347356.

  • 13.

    PlateKHMennelHD. Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol1995;47:8994.

  • 14.

    BullittEReardonDASmithJK. A review of micro- and macrovascular analyses in the assessment of tumor-associated vasculature as visualized by MR. Neuroimage2007;37(Suppl 1):S116119.

    • Search Google Scholar
    • Export Citation
  • 15.

    HobbsSKMonskyWLYuanF. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A1998;95:46074612.

    • Search Google Scholar
    • Export Citation
  • 16.

    MorikawaSBalukPKaidohT. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol2002;160:9851000.

  • 17.

    BalukPMorikawaSHaskellA. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol2003;163:18011815.

    • Search Google Scholar
    • Export Citation
  • 18.

    InaiTMancusoMHashizumeH. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol2004;165:3552.

    • Search Google Scholar
    • Export Citation
  • 19.

    RongYDurdenDLVan MeirEG. `Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol2006;65:529539.

    • Search Google Scholar
    • Export Citation
  • 20.

    JainRKdi TomasoEDudaDG. Angiogenesis in brain tumours. Nat Rev Neurosci2007;8:610622.

  • 21.

    KaurBKhwajaFWSeversonEA. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol2005;7:134153.

    • Search Google Scholar
    • Export Citation
  • 22.

    MaityAPoreNLeeJ. Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3'-kinase and distinct from that induced by hypoxia. Cancer Res2000;60:58795886.

    • Search Google Scholar
    • Export Citation
  • 23.

    PoreNLiuSHaas-KoganDA. PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res2003;63:236241.

    • Search Google Scholar
    • Export Citation
  • 24.

    SchmidtNOWestphalMHagelC. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer1999;84:1018.

    • Search Google Scholar
    • Export Citation
  • 25.

    AbounaderRLaterraJ. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol2005;7:436451.

  • 26.

    ReissYMacheinMRPlateKH. The role of angiopoietins during angiogenesis in gliomas. Brain Pathol2005;15:311317.

  • 27.

    WangLFFokasEJurickoJ. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. BMC Cancer2008;8:79.

    • Search Google Scholar
    • Export Citation
  • 28.

    BratDJBellailACVan MeirEG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol2005;7:122133.

    • Search Google Scholar
    • Export Citation
  • 29.

    ZagzagDZhongHScalzittiJM. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer2000;88:26062618.

    • Search Google Scholar
    • Export Citation
  • 30.

    ZhouYHTanFHessKR. The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res2003;9:33693375.

    • Search Google Scholar
    • Export Citation
  • 31.

    FlynnJRWangLGillespieDL. Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme. Cancer2008;113:10321042.

    • Search Google Scholar
    • Export Citation
  • 32.

    KowanetzMFerraraN. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res2006;12:50185022.

  • 33.

    ItalianoJEJrRichardsonJLPatel-HettS. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood2008;111:12271233.

    • Search Google Scholar
    • Export Citation
  • 34.

    EllisLM. The role of neuropilins in cancer. Mol Cancer Ther2006;5:10991107.

  • 35.

    HicklinDJEllisLM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol2005;23:10111027.

    • Search Google Scholar
    • Export Citation
  • 36.

    HuangHHeld-FeindtJBuhlR. Expression of VEGF and its receptors in different brain tumors. Neurol Res2005;27:371377.

  • 37.

    LinEYPollardJW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res2007;67:50645066.

  • 38.

    De PalmaMVenneriMAGalliR. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell2005;8:211226.

    • Search Google Scholar
    • Export Citation
  • 39.

    YangLDeBuskLMFukudaK. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell2004;6:409421.

    • Search Google Scholar
    • Export Citation
  • 40.

    HattoriKHeissigBWuY. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med2002;8:841849.

    • Search Google Scholar
    • Export Citation
  • 41.

    RempelSADudasSGeS. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res2000;6:102111.

    • Search Google Scholar
    • Export Citation
  • 42.

    RafatNBeckGSchulteJ. Circulating endothelial progenitor cells in malignant gliomas. J Neurosurg2010;112:4349.

  • 43.

    DudaDGCohenKSKozinSV. Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood2006;107:27742776.

    • Search Google Scholar
    • Export Citation
  • 44.

    SantarelliJGUdaniVYungYC. Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in the mouse brain. Neurosurgery2006;59:374382.

    • Search Google Scholar
    • Export Citation
  • 45.

    DuRLuKVPetritschC. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell2008;13:206220.

    • Search Google Scholar
    • Export Citation
  • 46.

    ShakedYHenkeERoodhartJM. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell2008;14:263273.

    • Search Google Scholar
    • Export Citation
  • 47.

    HeissigBRafiiSAkiyamaH. Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med2005;202:739750.

    • Search Google Scholar
    • Export Citation
  • 48.

    MooreXLLuJSunL. Endothelial progenitor cells' ``homing'' specificity to brain tumors. Gene Ther2004;11:811818.

  • 49.

    ZhengPPHopWCLuiderTM. Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann Neurol2007;62:4048.

    • Search Google Scholar
    • Export Citation
  • 50.

    FolkinsCManSXuP. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res2007;67:35603564.

    • Search Google Scholar
    • Export Citation
  • 51.

    KozinSVKamounWSHuangY. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res2010;70:56795685.

    • Search Google Scholar
    • Export Citation
  • 52.

    BaoSWuQSathornsumeteeS. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res2006;66:78437848.

    • Search Google Scholar
    • Export Citation
  • 53.

    CalabreseCPoppletonHKocakM. A perivascular niche for brain tumor stem cells. Cancer Cell2007;11:6982.

  • 54.

    FolkinsCShakedYManS. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res2009;69:72437251.

    • Search Google Scholar
    • Export Citation
  • 55.

    Ricci-VitianiLPalliniRBiffoniM. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature2010;468:824828.

    • Search Google Scholar
    • Export Citation
  • 56.

    WangRChadalavadaKWilshireJ. Glioblastoma stem-like cells give rise to tumour endothelium. Nature2010;468:829833.

  • 57.

    MargolinKGordonMSHolmgrenE. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol2001;19:851856.

    • Search Google Scholar
    • Export Citation
  • 58.

    GordonMSMargolinKTalpazM. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol2001;19:843850.

    • Search Google Scholar
    • Export Citation
  • 59.

    KimKJLiBWinerJ. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature1993;362:841844.

    • Search Google Scholar
    • Export Citation
  • 60.

    RubensteinJLKimJOzawaT. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia2000;2:306314.

    • Search Google Scholar
    • Export Citation
  • 61.

    LeeCGHeijnMdi TomasoE. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res2000;60:55655570.

    • Search Google Scholar
    • Export Citation
  • 62.

    JahnkeKMuldoonLLVarallyayCG. Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model. Neuro Oncol2009;11:142150.

    • Search Google Scholar
    • Export Citation
  • 63.

    MathieuVDe NeveNLe MercierM. Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia2008;10:13831392.

    • Search Google Scholar
    • Export Citation
  • 64.

    HurwitzHFehrenbacherLNovotnyW. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 65.

    Stark-VanceV. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma [abstract]. Neuro Oncol2005;7:Abstract 369.

  • 66.

    MacdonaldDRCascinoTLScholdSCJr. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol1990;8:12771280.

    • Search Google Scholar
    • Export Citation
  • 67.

    TherassePArbuckSGEisenhauerEA. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst2000;92:205216.

    • Search Google Scholar
    • Export Citation
  • 68.

    WickWWellerMvan den BentM. Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol2010;28:e188189; author reply e190–192.

    • Search Google Scholar
    • Export Citation
  • 69.

    RaizerJJGrimmSChamberlainMC. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer2010;116:52975305.

    • Search Google Scholar
    • Export Citation
  • 70.

    ChamberlainMCJohnstonSK. Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neurooncol2010;96:259269.

  • 71.

    FrancesconiABDupreSMatosM. Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci2010;17:970974.

    • Search Google Scholar
    • Export Citation
  • 72.

    ReardonDADesjardinsAVredenburghJJ. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer2009;101:19861994.

    • Search Google Scholar
    • Export Citation
  • 73.

    KangTYJinTElinzanoH. Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J Neurooncol2008;89:113118.

    • Search Google Scholar
    • Export Citation
  • 74.

    ZunigaRMTorcuatorRJainR. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol2009;91:329336.

    • Search Google Scholar
    • Export Citation
  • 75.

    AliSAMcHaylehWMAhmadA. Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J Neurosurg2008;109:268272.

    • Search Google Scholar
    • Export Citation
  • 76.

    BoksteinFShpigelSBlumenthalDT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer2008;112:22672273.

    • Search Google Scholar
    • Export Citation
  • 77.

    HasselbalchBLassenUHansenS. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol2010;12:508516.

    • Search Google Scholar
    • Export Citation
  • 78.

    NghiemphuPLLiuWLeeY. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology2009;72:12171222.

    • Search Google Scholar
    • Export Citation
  • 79.

    NordenADYoungGSSetayeshK. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology2008;70:779787.

    • Search Google Scholar
    • Export Citation
  • 80.

    PopeWBLaiANghiemphuP. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology2006;66:12581260.

  • 81.

    GutinPHIwamotoFMBealK. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys2009;75:156163.

    • Search Google Scholar
    • Export Citation
  • 82.

    SathornsumeteeSDesjardinsAVredenburghJJ. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol2010;12:13001310.

    • Search Google Scholar
    • Export Citation
  • 83.

    HolashJDavisSPapadopoulosN. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A2002;99:1139311398.

  • 84.

    KonnerJDupontJ. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer2004;4(Suppl 2):S8185.

    • Search Google Scholar
    • Export Citation
  • 85.

    Gomez-ManzanoCHolashJFueyoJ. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol2008;10:940945.

  • 86.

    WachsbergerPRBurdRCardiC. VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys2007;67:15261537.

    • Search Google Scholar
    • Export Citation
  • 87.

    LockhartACRothenbergMLDupontJ. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol2010;28:207214.

    • Search Google Scholar
    • Export Citation
  • 88.

    De GrootJFWenPYLambornK. Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601 [abstract]. J Clin Oncol2008;26(Suppl 1):Abstract 2020.

    • Search Google Scholar
    • Export Citation
  • 89.

    de BouardSHerlinPChristensenJG. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol2007;9:412423.

    • Search Google Scholar
    • Export Citation
  • 90.

    HilbergFRothGJKrssakM. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res2008;68:47744782.

    • Search Google Scholar
    • Export Citation
  • 91.

    RichJNSathornsumeteeSKeirST. ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clin Cancer Res2005;11:81458157.

    • Search Google Scholar
    • Export Citation
  • 92.

    YiinJJHuBSchornackPA. ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFR-vIII, in the brain. Mol Cancer Ther2010;9:929941.

    • Search Google Scholar
    • Export Citation
  • 93.

    YangFBrownCBuettnerR. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther2010;9:953962.

    • Search Google Scholar
    • Export Citation
  • 94.

    ZhangYGuessousFKofmanA. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs2010;13:112121.

    • Search Google Scholar
    • Export Citation
  • 95.

    SchuenemanAJHimmelfarbEGengL. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res2003;63:40094016.

    • Search Google Scholar
    • Export Citation
  • 96.

    DamianoVMelisiDBiancoC. Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. Clin Cancer Res2005;11:56395644.

    • Search Google Scholar
    • Export Citation
  • 97.

    ZhouQGuoPGalloJM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res2008;14:15401549.

    • Search Google Scholar
    • Export Citation
  • 98.

    BatchelorTTDudaDGdi TomasoE. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol2010;28:28172823.

    • Search Google Scholar
    • Export Citation
  • 99.

    BatchelorTTSorensenAGdi TomasoE. AZD2171, a Pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell2007;11:8395.

    • Search Google Scholar
    • Export Citation
  • 100.

    BatchelorTMulhollandPNeynsB. A phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine alone in recurrent glioblastoma patients [abstract]. Ann Oncol2010;21(Suppl 8):Abstract LBA7.

    • Search Google Scholar
    • Export Citation
  • 101.

    IwamotoFMLambornKRRobinsHI. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro Oncol2010;12:855861.

    • Search Google Scholar
    • Export Citation
  • 102.

    NeynsBSadonesJChaskisC. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol2010; in press.

  • 103.

    ReardonDAEgorinMJDesjardinsA. Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer2009;115:21882198.

    • Search Google Scholar
    • Export Citation
  • 104.

    HainsworthJDErvinTFriedmanE. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer2010;116:36633669.

    • Search Google Scholar
    • Export Citation
  • 105.

    DrappatzJNordenADWongET. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys2010;78:8590.

    • Search Google Scholar
    • Export Citation
  • 106.

    BrandesAAStuppRHauP. EORTC study 26041-22041: phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma. Eur J Cancer2010;46:348354.

    • Search Google Scholar
    • Export Citation
  • 107.

    HsuJYWakeleeHA. Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs2009;23:289304.

    • Search Google Scholar
    • Export Citation
  • 108.

    DineenSPSullivanLABeckAW. The adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer. BMC Cancer2008;8:352.

    • Search Google Scholar
    • Export Citation
  • 109.

    HuangHBhatAWoodnuttG. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer2010;10:575585.

  • 110.

    DingHRoncariLWuX. Expression and hypoxic regulation of angiopoietins in human astrocytomas. Neuro Oncol2001;3:110.

  • 111.

    StratmannARisauWPlateKH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol1998;153:14591466.

    • Search Google Scholar
    • Export Citation
  • 112.

    ZagzagDHooperAFriedlanderDR. In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol1999;159:391400.

    • Search Google Scholar
    • Export Citation
  • 113.

    ZadehGKoushanKPilloL. Role of Ang1 and its interaction with VEGF-A in astrocytomas. J Neuropathol Exp Neurol2004;63:978989.

  • 114.

    VilleneuveJGalarneauHBeaudetMJ. Reduced glioma growth following dexamethasone or anti-angiopoietin 2 treatment. Brain Pathol2008;18:401414.

    • Search Google Scholar
    • Export Citation
  • 115.

    OlinerJMinHLealJ. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell2004;6:507516.

  • 116.

    HerbstRSHongDChapL. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol2009;27:35573565.

    • Search Google Scholar
    • Export Citation
  • 117.

    WongETBremS. Antiangiogenesis treatment for glioblastoma multiforme: challenges and opportunities. J Natl Compr Canc Netw2008;6:515522.

    • Search Google Scholar
    • Export Citation
  • 118.

    XiongJPStehleTZhangR. Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science2002;296:151155.

    • Search Google Scholar
    • Export Citation
  • 119.

    BelloLFrancoliniMMarthynP. Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery2001;49:380389; discussion 390.

    • Search Google Scholar
    • Export Citation
  • 120.

    GladsonCL. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol1996;55:11431149.

    • Search Google Scholar
    • Export Citation
  • 121.

    GladsonCL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol1999;58:10291040.

  • 122.

    VitoloDParadisoPUcciniS. Expression of adhesion molecules and extracellular matrix proteins in glioblastomas: relation to angiogenesis and spread. Histopathology1996;28:521528.

    • Search Google Scholar
    • Export Citation
  • 123.

    DesgrosellierJSChereshDA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer2010;10:922.

  • 124.

    AvraamidesCJGarmy-SusiniBVarnerJA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer2008;8:604617.

  • 125.

    GladsonCLChereshDA. Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest1991;88:19241932.

    • Search Google Scholar
    • Export Citation
  • 126.

    MacDonaldTJTagaTShimadaH. Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery2001;48:151157.

    • Search Google Scholar
    • Export Citation
  • 127.

    MikkelsenTBrodieCFinnissS. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer2009;124:27192727.

    • Search Google Scholar
    • Export Citation
  • 128.

    YamadaSBuXYKhankaldyyanV. Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery2006;59:13041312; discussion 1312.

    • Search Google Scholar
    • Export Citation
  • 129.

    NaborsLBMikkelsenTBatchelorT. NABTT 0306: a randomized phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM) [abstract]. J Clin Oncol2009;27(Suppl 1):Abstract 2001.

    • Search Google Scholar
    • Export Citation
  • 130.

    NaborsLBMikkelsenTRosenfeldSS. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol2007;25:16511657.

    • Search Google Scholar
    • Export Citation
  • 131.

    ReardonDAFinkKLMikkelsenT. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol2008;26:56105617.

    • Search Google Scholar
    • Export Citation
  • 132.

    StuppRHegiMENeynsB. 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 Oncol2010;28:27122718.

    • Search Google Scholar
    • Export Citation
  • 133.

    MacDonaldTJStewartCFKocakM. Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012. J Clin Oncol2008;26:919924.

    • Search Google Scholar
    • Export Citation
  • 134.

    SorensenAGBatchelorTTWenPY. Response criteria for glioma. Nat Clin Pract Oncol2008;5:634644.

  • 135.

    van den BentMJVogelbaumMAWenPY. End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's criteria. J Clin Oncol2009;27:29052908.

    • Search Google Scholar
    • Export Citation
  • 136.

    WenPYMacdonaldDRReardonDA. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol2010;28:19631972.

    • Search Google Scholar
    • Export Citation
  • 137.

    JainRScarpaceLMEllikaS. Imaging response criteria for recurrent gliomas treated with bevacizumab: role of diffusion weighted imaging as an imaging biomarker. J Neurooncol2010;96:423431.

    • Search Google Scholar
    • Export Citation
  • 138.

    PopeWBKimHJHuoJ. Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology2009;252:182189.

    • Search Google Scholar
    • Export Citation
  • 139.

    SorensenAGBatchelorTTZhangWT. A ``vascular normalization index'' as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res2009;69:52965300.

    • Search Google Scholar
    • Export Citation
  • 140.

    ChenWDelaloyeSSilvermanDH. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol2007;25:47144721.

    • Search Google Scholar
    • Export Citation
  • 141.

    YamamotoYWongTZTurkingtonTG. 3'-Deoxy-3'-[F-18] fluorothymidine positron emission tomography in patients with recurrent glioblastoma multiforme: comparison with Gd-DT-PA enhanced magnetic resonance imaging. Mol Imaging Biol2006;8:340347.

    • Search Google Scholar
    • Export Citation
  • 142.

    ChoiSJKimJSKimJH. [18F]3'-deoxy-3'-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging2005;32:653659.

    • Search Google Scholar
    • Export Citation
  • 143.

    MotzerRJMichaelsonMDRedmanBG. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol2006;24:1624.

    • Search Google Scholar
    • Export Citation
  • 144.

    WillettCGBoucherYDudaDG. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol2005;23:81368139.

    • Search Google Scholar
    • Export Citation
  • 145.

    BertoliniFShakedYMancusoP. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer2006;6:835845.

    • Search Google Scholar
    • Export Citation
  • 146.

    SathornsumeteeSCaoYMarcelloJE. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol2008;26:271278.

    • Search Google Scholar
    • Export Citation
  • 147.

    HasselbalchBEriksenJGBroholmH. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS2010;118:585594.

    • Search Google Scholar
    • Export Citation
  • 148.

    ReardonDADesjardinsAPetersK. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol2010; in press.

    • Search Google Scholar
    • Export Citation
  • 149.

    QuantECNordenADDrappatzJ. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol2009;11:550555.

    • Search Google Scholar
    • Export Citation
  • 150.

    IwamotoFMAbreyLEBealK. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology2009;73:12001206.

    • Search Google Scholar
    • Export Citation
  • 151.

    BergersGHanahanD. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer2008;8:592603.

  • 152.

    EbosJMLeeCRKerbelRS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res2009;15:50205025.

    • Search Google Scholar
    • Export Citation
  • 153.

    EbosJMLeeCRChristensenJG. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A2007;104:1706917074.

    • Search Google Scholar
    • Export Citation
  • 154.

    Paez-RibesMAllenEHudockJ. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell2009;15:220231.

    • Search Google Scholar
    • Export Citation
  • 155.

    LamszusKKunkelPWestphalM. Invasion as limitation to antiangiogenic glioma therapy. Acta Neurochir Suppl2003;88:169177.

  • 156.

    KunkelPUlbrichtUBohlenP. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res2001;61:66246628.

    • Search Google Scholar
    • Export Citation
  • 157.

    KamounWSLeyCDFarrarCT. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol2009;27:25422552.

    • Search Google Scholar
    • Export Citation
  • 158.

    NarayanaAKellyPGolfinosJ. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg2009;110:173180.

    • Search Google Scholar
    • Export Citation
  • 159.

    de GrootJFFullerGKumarAJ. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol2010;12:233242.

    • Search Google Scholar
    • Export Citation
  • 160.

    GerstnerERChenPJWenPY. Infiltrative patterns of glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro Oncol2010;12:466472.

    • Search Google Scholar
    • Export Citation
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