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

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  • a From the Departments of Surgery, Pediatrics, Medicine, Pathology, Cancer Center Biostatistics, and Radiation Oncology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.
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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.

    Stupp R, Mason WP, van den Bent MJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987996.

  • 2.

    Ballman KV, Buckner JC, Brown PD. 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 Oncol 2007;9:2938.

    • Search Google Scholar
    • Export Citation
  • 3.

    Lamborn KR, Yung WK, Chang SM. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 2008;10:162170.

    • Search Google Scholar
    • Export Citation
  • 4.

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

    • Search Google Scholar
    • Export Citation
  • 5.

    Reardon DA, Rich JN, Friedman HS. Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 2006;24:12531265.

  • 6.

    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492507.

  • 7.

    Ferrara N, Hillan KJ, Gerber HP. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391400.

    • Search Google Scholar
    • Export Citation
  • 8.

    Friedman HS, Prados MD, Wen PY. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:47334740.

    • Search Google Scholar
    • Export Citation
  • 9.

    Kreisl TN, Kim L, Moore K. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740745.

    • Search Google Scholar
    • Export Citation
  • 10.

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

    • Search Google Scholar
    • Export Citation
  • 11.

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

    • Search Google Scholar
    • Export Citation
  • 12.

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

  • 13.

    Plate KH, Mennel HD. Vascular morphology and angiogenesis in glial tumors. Exp Toxicol Pathol 1995;47:8994.

  • 14.

    Bullitt E, Reardon DA, Smith JK. A review of micro- and macrovascular analyses in the assessment of tumor-associated vasculature as visualized by MR. Neuroimage 2007;37(Suppl 1):S116119.

    • Search Google Scholar
    • Export Citation
  • 15.

    Hobbs SK, Monsky WL, Yuan F. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 1998;95:46074612.

    • Search Google Scholar
    • Export Citation
  • 16.

    Morikawa S, Baluk P, Kaidoh T. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 2002;160:9851000.

  • 17.

    Baluk P, Morikawa S, Haskell A. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 2003;163:18011815.

    • Search Google Scholar
    • Export Citation
  • 18.

    Inai T, Mancuso M, Hashizume H. 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 Pathol 2004;165:3552.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rong Y, Durden DL, Van Meir EG. `Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 2006;65:529539.

    • Search Google Scholar
    • Export Citation
  • 20.

    Jain RK, di Tomaso E, Duda DG. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610622.

  • 21.

    Kaur B, Khwaja FW, Severson EA. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 2005;7:134153.

    • Search Google Scholar
    • Export Citation
  • 22.

    Maity A, Pore N, Lee J. 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 Res 2000;60:58795886.

    • Search Google Scholar
    • Export Citation
  • 23.

    Pore N, Liu S, Haas-Kogan DA. 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 Res 2003;63:236241.

    • Search Google Scholar
    • Export Citation
  • 24.

    Schmidt NO, Westphal M, Hagel C. 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 Cancer 1999;84:1018.

    • Search Google Scholar
    • Export Citation
  • 25.

    Abounader R, Laterra J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol 2005;7:436451.

  • 26.

    Reiss Y, Machein MR, Plate KH. The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 2005;15:311317.

  • 27.

    Wang LF, Fokas E, Juricko J. Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. BMC Cancer 2008;8:79.

    • Search Google Scholar
    • Export Citation
  • 28.

    Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 2005;7:122133.

    • Search Google Scholar
    • Export Citation
  • 29.

    Zagzag D, Zhong H, Scalzitti JM. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer 2000;88:26062618.

    • Search Google Scholar
    • Export Citation
  • 30.

    Zhou YH, Tan F, Hess KR. The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res 2003;9:33693375.

    • Search Google Scholar
    • Export Citation
  • 31.

    Flynn JR, Wang L, Gillespie DL. Hypoxia-regulated protein expression, patient characteristics, and preoperative imaging as predictors of survival in adults with glioblastoma multiforme. Cancer 2008;113:10321042.

    • Search Google Scholar
    • Export Citation
  • 32.

    Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res 2006;12:50185022.

  • 33.

    Italiano JE Jr, Richardson JL, Patel-Hett S. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008;111:12271233.

    • Search Google Scholar
    • Export Citation
  • 34.

    Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther 2006;5:10991107.

  • 35.

    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
  • 36.

    Huang H, Held-Feindt J, Buhl R. Expression of VEGF and its receptors in different brain tumors. Neurol Res 2005;27:371377.

  • 37.

    Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 2007;67:50645066.

  • 38.

    De Palma M, Venneri MA, Galli R. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005;8:211226.

    • Search Google Scholar
    • Export Citation
  • 39.

    Yang L, DeBusk LM, Fukuda K. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004;6:409421.

    • Search Google Scholar
    • Export Citation
  • 40.

    Hattori K, Heissig B, Wu Y. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 2002;8:841849.

    • Search Google Scholar
    • Export Citation
  • 41.

    Rempel SA, Dudas S, Ge S. 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 Res 2000;6:102111.

    • Search Google Scholar
    • Export Citation
  • 42.

    Rafat N, Beck G, Schulte J. Circulating endothelial progenitor cells in malignant gliomas. J Neurosurg 2010;112:4349.

  • 43.

    Duda DG, Cohen KS, Kozin SV. Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood 2006;107:27742776.

    • Search Google Scholar
    • Export Citation
  • 44.

    Santarelli JG, Udani V, Yung YC. Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in the mouse brain. Neurosurgery 2006;59:374382.

    • Search Google Scholar
    • Export Citation
  • 45.

    Du R, Lu KV, Petritsch C. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008;13:206220.

    • Search Google Scholar
    • Export Citation
  • 46.

    Shaked Y, Henke E, Roodhart JM. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008;14:263273.

    • Search Google Scholar
    • Export Citation
  • 47.

    Heissig B, Rafii S, Akiyama H. Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 2005;202:739750.

    • Search Google Scholar
    • Export Citation
  • 48.

    Moore XL, Lu J, Sun L. Endothelial progenitor cells' ``homing'' specificity to brain tumors. Gene Ther 2004;11:811818.

  • 49.

    Zheng PP, Hop WC, Luider TM. Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann Neurol 2007;62:4048.

    • Search Google Scholar
    • Export Citation
  • 50.

    Folkins C, Man S, Xu P. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 2007;67:35603564.

    • Search Google Scholar
    • Export Citation
  • 51.

    Kozin SV, Kamoun WS, Huang Y. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 2010;70:56795685.

    • Search Google Scholar
    • Export Citation
  • 52.

    Bao S, Wu Q, Sathornsumetee S. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006;66:78437848.

    • Search Google Scholar
    • Export Citation
  • 53.

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

  • 54.

    Folkins C, Shaked Y, Man S. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res 2009;69:72437251.

    • Search Google Scholar
    • Export Citation
  • 55.

    Ricci-Vitiani L, Pallini R, Biffoni M. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010;468:824828.

    • Search Google Scholar
    • Export Citation
  • 56.

    Wang R, Chadalavada K, Wilshire J. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010;468:829833.

  • 57.

    Margolin K, Gordon MS, Holmgren E. 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 Oncol 2001;19:851856.

    • Search Google Scholar
    • Export Citation
  • 58.

    Gordon MS, Margolin K, Talpaz M. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843850.

    • Search Google Scholar
    • Export Citation
  • 59.

    Kim KJ, Li B, Winer J. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841844.

    • Search Google Scholar
    • Export Citation
  • 60.

    Rubenstein JL, Kim J, Ozawa T. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2000;2:306314.

    • Search Google Scholar
    • Export Citation
  • 61.

    Lee CG, Heijn M, di Tomaso E. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:55655570.

    • Search Google Scholar
    • Export Citation
  • 62.

    Jahnke K, Muldoon LL, Varallyay CG. Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model. Neuro Oncol 2009;11:142150.

    • Search Google Scholar
    • Export Citation
  • 63.

    Mathieu V, De Neve N, Le Mercier M. Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia 2008;10:13831392.

    • Search Google Scholar
    • Export Citation
  • 64.

    Hurwitz H, Fehrenbacher L, Novotny W. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:23352342.

    • Search Google Scholar
    • Export Citation
  • 65.

    Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma [abstract]. Neuro Oncol 2005;7:Abstract 369.

  • 66.

    Macdonald DR, Cascino 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
  • 67.

    Therasse P, Arbuck SG, Eisenhauer EA. 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 Inst 2000;92:205216.

    • Search Google Scholar
    • Export Citation
  • 68.

    Wick W, Weller M, van den Bent M. Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol 2010;28:e188189; author reply e190–192.

    • Search Google Scholar
    • Export Citation
  • 69.

    Raizer JJ, Grimm S, Chamberlain MC. A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 2010;116:52975305.

    • Search Google Scholar
    • Export Citation
  • 70.

    Chamberlain MC, Johnston SK. Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neurooncol 2010;96:259269.

  • 71.

    Francesconi AB, Dupre S, Matos M. Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci 2010;17:970974.

    • Search Google Scholar
    • Export Citation
  • 72.

    Reardon DA, Desjardins A, Vredenburgh JJ. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 2009;101:19861994.

    • Search Google Scholar
    • Export Citation
  • 73.

    Kang TY, Jin T, Elinzano H. Irinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safety. J Neurooncol 2008;89:113118.

    • Search Google Scholar
    • Export Citation
  • 74.

    Zuniga RM, Torcuator R, Jain R. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 2009;91:329336.

    • Search Google Scholar
    • Export Citation
  • 75.

    Ali SA, McHayleh WM, Ahmad A. Bevacizumab and irinotecan therapy in glioblastoma multiforme: a series of 13 cases. J Neurosurg 2008;109:268272.

    • Search Google Scholar
    • Export Citation
  • 76.

    Bokstein F, Shpigel S, Blumenthal DT. Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 2008;112:22672273.

    • Search Google Scholar
    • Export Citation
  • 77.

    Hasselbalch B, Lassen U, Hansen S. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol 2010;12:508516.

    • Search Google Scholar
    • Export Citation
  • 78.

    Nghiemphu PL, Liu W, Lee Y. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 2009;72:12171222.

    • Search Google Scholar
    • Export Citation
  • 79.

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

    • Search Google Scholar
    • Export Citation
  • 80.

    Pope WB, Lai A, Nghiemphu P. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 2006;66:12581260.

  • 81.

    Gutin PH, Iwamoto FM, Beal K. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009;75:156163.

    • Search Google Scholar
    • Export Citation
  • 82.

    Sathornsumetee S, Desjardins A, Vredenburgh JJ. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 2010;12:13001310.

    • Search Google Scholar
    • Export Citation
  • 83.

    Holash J, Davis S, Papadopoulos N. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002;99:1139311398.

  • 84.

    Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer 2004;4(Suppl 2):S8185.

    • Search Google Scholar
    • Export Citation
  • 85.

    Gomez-Manzano C, Holash J, Fueyo J. VEGF Trap induces antiglioma effect at different stages of disease. Neuro Oncol 2008;10:940945.

  • 86.

    Wachsberger PR, Burd R, Cardi C. VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys 2007;67:15261537.

    • Search Google Scholar
    • Export Citation
  • 87.

    Lockhart AC, Rothenberg ML, Dupont J. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010;28:207214.

    • Search Google Scholar
    • Export Citation
  • 88.

    De Groot JF, Wen PY, Lamborn K. Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601 [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 2020.

    • Search Google Scholar
    • Export Citation
  • 89.

    de Bouard S, Herlin P, Christensen JG. Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 2007;9:412423.

    • Search Google Scholar
    • Export Citation
  • 90.

    Hilberg F, Roth GJ, Krssak M. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008;68:47744782.

    • Search Google Scholar
    • Export Citation
  • 91.

    Rich JN, Sathornsumetee S, Keir ST. 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 Res 2005;11:81458157.

    • Search Google Scholar
    • Export Citation
  • 92.

    Yiin JJ, Hu B, Schornack PA. 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 Ther 2010;9:929941.

    • Search Google Scholar
    • Export Citation
  • 93.

    Yang F, Brown C, Buettner R. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol Cancer Ther 2010;9:953962.

    • Search Google Scholar
    • Export Citation
  • 94.

    Zhang Y, Guessous F, Kofman A. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs 2010;13:112121.

    • Search Google Scholar
    • Export Citation
  • 95.

    Schueneman AJ, Himmelfarb E, Geng L. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res 2003;63:40094016.

    • Search Google Scholar
    • Export Citation
  • 96.

    Damiano V, Melisi D, Bianco C. Cooperative antitumor effect of multitargeted kinase inhibitor ZD6474 and ionizing radiation in glioblastoma. Clin Cancer Res 2005;11:56395644.

    • Search Google Scholar
    • Export Citation
  • 97.

    Zhou Q, Guo P, Gallo JM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res 2008;14:15401549.

    • Search Google Scholar
    • Export Citation
  • 98.

    Batchelor TT, Duda DG, di Tomaso E. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010;28:28172823.

    • Search Google Scholar
    • Export Citation
  • 99.

    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
  • 100.

    Batchelor T, Mulholland P, Neyns B. 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 Oncol 2010;21(Suppl 8):Abstract LBA7.

    • Search Google Scholar
    • Export Citation
  • 101.

    Iwamoto FM, Lamborn KR, Robins HI. 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 Oncol 2010;12:855861.

    • Search Google Scholar
    • Export Citation
  • 102.

    Neyns B, Sadones J, Chaskis C. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 2010; in press.

  • 103.

    Reardon DA, Egorin MJ, Desjardins A. Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 2009;115:21882198.

    • Search Google Scholar
    • Export Citation
  • 104.

    Hainsworth JD, Ervin T, Friedman E. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer 2010;116:36633669.

    • Search Google Scholar
    • Export Citation
  • 105.

    Drappatz J, Norden AD, Wong ET. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 2010;78:8590.

    • Search Google Scholar
    • Export Citation
  • 106.

    Brandes AA, Stupp R, Hau P. 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 Cancer 2010;46:348354.

    • Search Google Scholar
    • Export Citation
  • 107.

    Hsu JY, Wakelee HA. Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs 2009;23:289304.

    • Search Google Scholar
    • Export Citation
  • 108.

    Dineen SP, Sullivan LA, Beck AW. The adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer. BMC Cancer 2008;8:352.

    • Search Google Scholar
    • Export Citation
  • 109.

    Huang H, Bhat A, Woodnutt G. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 2010;10:575585.

  • 110.

    Ding H, Roncari L, Wu X. Expression and hypoxic regulation of angiopoietins in human astrocytomas. Neuro Oncol 2001;3:110.

  • 111.

    Stratmann A, Risau W, Plate KH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 1998;153:14591466.

    • Search Google Scholar
    • Export Citation
  • 112.

    Zagzag D, Hooper A, Friedlander DR. In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 1999;159:391400.

    • Search Google Scholar
    • Export Citation
  • 113.

    Zadeh G, Koushan K, Pillo L. Role of Ang1 and its interaction with VEGF-A in astrocytomas. J Neuropathol Exp Neurol 2004;63:978989.

  • 114.

    Villeneuve J, Galarneau H, Beaudet MJ. Reduced glioma growth following dexamethasone or anti-angiopoietin 2 treatment. Brain Pathol 2008;18:401414.

    • Search Google Scholar
    • Export Citation
  • 115.

    Oliner J, Min H, Leal J. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 2004;6:507516.

  • 116.

    Herbst RS, Hong D, Chap L. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol 2009;27:35573565.

    • Search Google Scholar
    • Export Citation
  • 117.

    Wong ET, Brem S. Antiangiogenesis treatment for glioblastoma multiforme: challenges and opportunities. J Natl Compr Canc Netw 2008;6:515522.

    • Search Google Scholar
    • Export Citation
  • 118.

    Xiong JP, Stehle T, Zhang R. Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 2002;296:151155.

    • Search Google Scholar
    • Export Citation
  • 119.

    Bello L, Francolini M, Marthyn P. Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 2001;49:380389; discussion 390.

    • Search Google Scholar
    • Export Citation
  • 120.

    Gladson CL. Expression of integrin alpha v beta 3 in small blood vessels of glioblastoma tumors. J Neuropathol Exp Neurol 1996;55:11431149.

    • Search Google Scholar
    • Export Citation
  • 121.

    Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol 1999;58:10291040.

  • 122.

    Vitolo D, Paradiso P, Uccini S. Expression of adhesion molecules and extracellular matrix proteins in glioblastomas: relation to angiogenesis and spread. Histopathology 1996;28:521528.

    • Search Google Scholar
    • Export Citation
  • 123.

    Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10:922.

  • 124.

    Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008;8:604617.

  • 125.

    Gladson CL, Cheresh DA. Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 1991;88:19241932.

    • Search Google Scholar
    • Export Citation
  • 126.

    MacDonald TJ, Taga T, Shimada H. Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 2001;48:151157.

    • Search Google Scholar
    • Export Citation
  • 127.

    Mikkelsen T, Brodie C, Finniss S. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 2009;124:27192727.

    • Search Google Scholar
    • Export Citation
  • 128.

    Yamada S, Bu XY, Khankaldyyan V. Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery 2006;59:13041312; discussion 1312.

    • Search Google Scholar
    • Export Citation
  • 129.

    Nabors LB, Mikkelsen T, Batchelor T. 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 Oncol 2009;27(Suppl 1):Abstract 2001.

    • Search Google Scholar
    • Export Citation
  • 130.

    Nabors LB, Mikkelsen T, Rosenfeld SS. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 2007;25:16511657.

    • Search Google Scholar
    • Export Citation
  • 131.

    Reardon DA, Fink KL, Mikkelsen T. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008;26:56105617.

    • Search Google Scholar
    • Export Citation
  • 132.

    Stupp R, Hegi ME, Neyns B. 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 2010;28:27122718.

    • Search Google Scholar
    • Export Citation
  • 133.

    MacDonald TJ, Stewart CF, Kocak M. Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012. J Clin Oncol 2008;26:919924.

    • Search Google Scholar
    • Export Citation
  • 134.

    Sorensen AG, Batchelor TT, Wen PY. Response criteria for glioma. Nat Clin Pract Oncol 2008;5:634644.

  • 135.

    van den Bent MJ, Vogelbaum MA, Wen PY. End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's criteria. J Clin Oncol 2009;27:29052908.

    • Search Google Scholar
    • Export Citation
  • 136.

    Wen PY, Macdonald DR, Reardon DA. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol 2010;28:19631972.

    • Search Google Scholar
    • Export Citation
  • 137.

    Jain R, Scarpace LM, Ellika S. Imaging response criteria for recurrent gliomas treated with bevacizumab: role of diffusion weighted imaging as an imaging biomarker. J Neurooncol 2010;96:423431.

    • Search Google Scholar
    • Export Citation
  • 138.

    Pope WB, Kim HJ, Huo J. Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 2009;252:182189.

    • Search Google Scholar
    • Export Citation
  • 139.

    Sorensen AG, Batchelor TT, Zhang WT. A ``vascular normalization index'' as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 2009;69:52965300.

    • Search Google Scholar
    • Export Citation
  • 140.

    Chen W, Delaloye S, Silverman DH. 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
  • 141.

    Yamamoto Y, Wong TZ, Turkington TG. 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 Biol 2006;8:340347.

    • Search Google Scholar
    • Export Citation
  • 142.

    Choi SJ, Kim JS, Kim JH. [18F]3'-deoxy-3'-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging 2005;32:653659.

    • Search Google Scholar
    • Export Citation
  • 143.

    Motzer RJ, Michaelson MD, Redman BG. 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 Oncol 2006;24:1624.

    • Search Google Scholar
    • Export Citation
  • 144.

    Willett CG, Boucher Y, Duda DG. 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 Oncol 2005;23:81368139.

    • Search Google Scholar
    • Export Citation
  • 145.

    Bertolini F, Shaked Y, Mancuso P. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 2006;6:835845.

    • Search Google Scholar
    • Export Citation
  • 146.

    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
  • 147.

    Hasselbalch B, Eriksen JG, Broholm H. Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS 2010;118:585594.

    • Search Google Scholar
    • Export Citation
  • 148.

    Reardon DA, Desjardins A, Peters K. Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol 2010; in press.

    • Search Google Scholar
    • Export Citation
  • 149.

    Quant EC, Norden AD, Drappatz J. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol 2009;11:550555.

    • Search Google Scholar
    • Export Citation
  • 150.

    Iwamoto FM, Abrey LE, Beal K. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 2009;73:12001206.

    • Search Google Scholar
    • Export Citation
  • 151.

    Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592603.

  • 152.

    Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 2009;15:50205025.

    • Search Google Scholar
    • Export Citation
  • 153.

    Ebos JM, Lee CR, Christensen JG. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 2007;104:1706917074.

    • Search Google Scholar
    • Export Citation
  • 154.

    Paez-Ribes M, Allen E, Hudock J. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220231.

    • Search Google Scholar
    • Export Citation
  • 155.

    Lamszus K, Kunkel P, Westphal M. Invasion as limitation to antiangiogenic glioma therapy. Acta Neurochir Suppl 2003;88:169177.

  • 156.

    Kunkel P, Ulbricht U, Bohlen P. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 2001;61:66246628.

    • Search Google Scholar
    • Export Citation
  • 157.

    Kamoun WS, Ley CD, Farrar CT. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 2009;27:25422552.

    • Search Google Scholar
    • Export Citation
  • 158.

    Narayana A, Kelly P, Golfinos J. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg 2009;110:173180.

    • Search Google Scholar
    • Export Citation
  • 159.

    de Groot JF, Fuller G, Kumar AJ. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 2010;12:233242.

    • Search Google Scholar
    • Export Citation
  • 160.

    Gerstner ER, Chen PJ, Wen PY. Infiltrative patterns of glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro Oncol 2010;12:466472.

    • Search Google Scholar
    • Export Citation
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