Skip to main content
PMC home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Jul;6(3):513–526. doi: 10.1016/j.nurt.2009.04.010

Antiangiogenic strategies for treatment of malignant gliomas

Andrew S Chi 1,2,3, Andrew D Norden 2,3,4,5, Patrick Y Wen 2,3,4,5,✉
PMCID: PMC5084187  PMID: 19560741

Summary

Numerous antiangiogenic agents with diverse mechanisms of action are currently under investigation for the treatment of patients with glioblastoma (GBM), a diagnosis that continues to carry a poor prognosis despite maximal conventional therapy. Early clinical trials suggest that antiangiogenic drugs, which target the blood vessels of these highly angiogenic tumors, may have clinical benefit in GBM patients. Antiangiogenic agents have potent antiedema and steroid-sparing effects in patients, and emerging data suggest that these drugs may modestly improve progression-free survival. Although these early results are encouraging, several issues arise regarding the use and efficacy of these agents. Interpretation of the radiographic changes that occur after treatment with antiangiogenic agents presents a major challenge. Still lacking are reliable radiographic and biologic markers that can predict which patients will benefit from treatment and that accurately indicate response and progression during therapy. In addition, most patients treated with antiangiogenic drugs eventually progress, and the mechanisms by which tumors escape from therapy are only beginning to be understood. Larger prospective trials that incorporate correlative biomarker studies will be required to address these challenges. Here, we summarize the clinical experience with antiangiogenic therapy in patients with malignant gliomas (MG), review the major issues concerning the use and development of these agents, and discuss strategies that may build upon the initial gains observed with antiangiogenic agents.

Key Words: Malignant glioma, glioblastoma, angiogenesis, vascular endothelial growth factor, edema, biomarker

References

  • 1.Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507. doi: 10.1056/NEJMra0708126. [DOI] [PubMed] [Google Scholar]
  • 2.Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330. [DOI] [PubMed] [Google Scholar]
  • 3.Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17:2572–2578. doi: 10.1200/JCO.1999.17.8.2572. [DOI] [PubMed] [Google Scholar]
  • 4.van de Beek D. Brain teasing effect of dexamethasone. Lancet Neurol. 2007;6:203–204. doi: 10.1016/S1474-4422(07)70041-8. [DOI] [PubMed] [Google Scholar]
  • 5.Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY. Medical management of brain tumor patients. Neurol Clin. 2007;25:1035–71. doi: 10.1016/j.ncl.2007.07.015. [DOI] [PubMed] [Google Scholar]
  • 6.Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
  • 7.Folkman J. Angiogenesis. Annu Rev Med. 2006;57:1–18. doi: 10.1146/annurev.med.57.121304.131306. [DOI] [PubMed] [Google Scholar]
  • 8.Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257. doi: 10.1038/35025220. [DOI] [PubMed] [Google Scholar]
  • 9.Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–2049. doi: 10.1056/NEJMra0706596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6:273–286. doi: 10.1038/nrd2115. [DOI] [PubMed] [Google Scholar]
  • 11.Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. doi: 10.1056/NEJMoa032691. [DOI] [PubMed] [Google Scholar]
  • 12.Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884. [DOI] [PubMed] [Google Scholar]
  • 13.Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676. doi: 10.1056/NEJMoa072113. [DOI] [PubMed] [Google Scholar]
  • 14.Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134. doi: 10.1056/NEJMoa060655. [DOI] [PubMed] [Google Scholar]
  • 15.Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. doi: 10.1056/NEJMoa0708857. [DOI] [PubMed] [Google Scholar]
  • 16.Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–124. doi: 10.1056/NEJMoa065044. [DOI] [PubMed] [Google Scholar]
  • 17.Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–1338. doi: 10.1016/S0140-6736(06)69446-4. [DOI] [PubMed] [Google Scholar]
  • 18.Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol. 2005;15:297–310. doi: 10.1111/j.1750-3639.2005.tb00115.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. J Neurooncol. 2006;78:281–293. doi: 10.1007/s11060-005-9097-6. [DOI] [PubMed] [Google Scholar]
  • 20.Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610–622. doi: 10.1038/nrn2175. [DOI] [PubMed] [Google Scholar]
  • 21.Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6:553–563. doi: 10.1016/j.ccr.2004.10.011. [DOI] [PubMed] [Google Scholar]
  • 22.Gagner JP, Law M, Fischer I, Newcomb EW, Zagzag D. Angiogenesis in gliomas: imaging and experimental therapeutics. Brain Pathol. 2005;15:342–363. doi: 10.1111/j.1750-3639.2005.tb00119.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Reardon DA, Desjardins A, Rich JN, Vredenburgh JJ. The emerging role of anti-angiogenic therapy for malignant glioma. Curr Treat Options Oncol. 2008;9:1–22. doi: 10.1007/s11864-008-0052-6. [DOI] [PubMed] [Google Scholar]
  • 24.Norden AD, Drappatz J, Wen PY. Antiangiogenic therapy in malignant gliomas. Curr Opin Oncol. 2008;20:652–661. doi: 10.1097/CCO.0b013e32831186ba. [DOI] [PubMed] [Google Scholar]
  • 25.Cloughesy TF, Prados MD, Wen PY, et al. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM) J Clin Oncol. 2008;26(20 Suppl):A2010b–A2010b. [Google Scholar]
  • 26.Jam RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol. 2006;3:24–40. doi: 10.1038/ncponc0403. [DOI] [PubMed] [Google Scholar]
  • 27.Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med. 2007;13:223–230. doi: 10.1016/j.molmed.2007.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603. doi: 10.1038/nrc2442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Macdonald DR, Cascino TL, Schold SCJ, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–1280. doi: 10.1200/JCO.1990.8.7.1277. [DOI] [PubMed] [Google Scholar]
  • 30.Sorensen AG, Batchelor TT, Wen PY, Zhang WT, Jain RK. Response criteria for glioma. Nat Clin Pract Oncol. 2008;5:634–644. doi: 10.1038/ncponc1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Vredenburgh JJ, Desjardins A, Herndon JEn, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13:1253–1259. doi: 10.1158/1078-0432.CCR-06-2309. [DOI] [PubMed] [Google Scholar]
  • 32.Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–4729. doi: 10.1200/JCO.2007.12.2440. [DOI] [PubMed] [Google Scholar]
  • 33.Wagner SA, Desjardins A, Reardon DA, et al. Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant gliomas. J Clin Oncol 2008;26 (May 20 Suppl):abstract 2021.
  • 34.Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83:588–593. doi: 10.1054/bjoc.2000.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Yung WK, Prados MD, Yaya-Tur R, Temodal Brain Tumor Group et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clm Oncol. 1999;17:2762–2771. doi: 10.1200/JCO.1999.17.9.2762. [DOI] [PubMed] [Google Scholar]
  • 36.Chen W, Delaloye S, Silverman DH, et al. 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;25:4714–4721. doi: 10.1200/JCO.2006.10.5825. [DOI] [PubMed] [Google Scholar]
  • 37.Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neuro Oncol. 2005;7:369–369. [Google Scholar]
  • 38.Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology. 2006;66:1258–1260. doi: 10.1212/01.wnl.0000208958.29600.87. [DOI] [PubMed] [Google Scholar]
  • 39.Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008;70:779–787. doi: 10.1212/01.wnl.0000304121.57857.38. [DOI] [PubMed] [Google Scholar]
  • 40.Guiu S, Taillibert S, Chinot O, et al. Bevacizumab/irinotecan: an active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF multicenter study [In French] Rev Neurol (Paris) 2008;164:588–594. doi: 10.1016/j.neurol.2008.04.003. [DOI] [PubMed] [Google Scholar]
  • 41.Batchelor TT, Gilbert MR, Supko JG, et al. Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neuro Oncol. 2004;6:21–27. doi: 10.1215/S1152851703000218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–745. doi: 10.1200/JCO.2008.16.3055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ballman KV, Buckner JC, Brown PD, et al. The relationship between six-month progression-free survival and 12-mouth overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncol. 2007;9:29–38. doi: 10.1215/15228517-2006-025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Narayana A, Kelly P, Golfinos J, et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg. 2009;110:173–180. doi: 10.3171/2008.4.17492. [DOI] [PubMed] [Google Scholar]
  • 45.Norden AD, Drappatz J, Muzikansky A, et al. An exploratory survival analysis of anti-angiogeuic therapy for recurrent malignant glioma. J Neurooncol. 2009;92:149–155. doi: 10.1007/s11060-008-9745-8. [DOI] [PubMed] [Google Scholar]
  • 46.Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99:11393–11398. doi: 10.1073/pnas.172398299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.De Groot JF, Wen PY, Lamborn K, et al. Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601. J Clm Oncol 2008;26(May 20 Suppl):abstract 2020.
  • 48.Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26:127–132. doi: 10.1038/nbt1358. [DOI] [PubMed] [Google Scholar]
  • 49.Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95. doi: 10.1016/j.ccr.2006.11.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Batchelor T, Sorensen G, di Tomaso E, et al. A multidisciplinary phase II study of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. AACR Meet Abstr 2008 (abstract LB-247).
  • 51.Gerstner ER, Duda DG, di Tomaso E, et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clm Oncol. 2009;6:229–236. doi: 10.1038/nrclinonc.2009.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. 2007;67:323–326. doi: 10.1016/j.ijrobp.2006.10.010. [DOI] [PubMed] [Google Scholar]
  • 53.Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol. 2007;82:81–83. doi: 10.1007/s11060-006-9241-y. [DOI] [PubMed] [Google Scholar]
  • 54.Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9:453–461. doi: 10.1016/S1470-2045(08)70125-6. [DOI] [PubMed] [Google Scholar]
  • 55.Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 2008;113:405–410. doi: 10.1002/cncr.23562. [DOI] [PubMed] [Google Scholar]
  • 56.Thomas AL, Morgan B, Horsfield MA, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol. 2005;23:4162–4171. doi: 10.1200/JCO.2005.09.034. [DOI] [PubMed] [Google Scholar]
  • 57.Conrad C, Friedman H, Reardon D, et al. A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM) J Clm Oncol. 2004;22:14S–14S. [Google Scholar]
  • 58.Reardon D, Friedman H, Brada M, et al. A Phase I/II trial of PTK 787/ZK 222584 (PTK/ZK), a multi-VEGF receptor tyrosine kinase inhibitor, in combination with either temozolomide or lo-mustine for patients with recurrent glioblastoma multiforme (GBM) Neuro Oncol. 2004;6:TA–48. [Google Scholar]
  • 59.Kirkpatrick JP, Rich JN, Vredenburgh JJ, et al. Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG). J Clin Oncol 2008;26(May 20 Suppl):abstract 2057.
  • 60.Morabito A, De Maio E, Di Maio M, Normanuo N, Perrone F. Tyrosine kinase inhibitors of vascular endotbelial growth factor receptors in clinical trials: current status and future directions. Oncologist. 2006;11:753–764. doi: 10.1634/theoncologist.11-7-753. [DOI] [PubMed] [Google Scholar]
  • 61.Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res. 2008;14:6371–6375. doi: 10.1158/1078-0432.CCR-07-5287. [DOI] [PubMed] [Google Scholar]
  • 62.D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082–4085. doi: 10.1073/pnas.91.9.4082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Marx GM, Pavlakis N, McCowatt S, et al. Phase II study of thalidomide in the treatment of recurrent glioblastoma multi-forme. J Neurooncol. 2001;54:31–38. doi: 10.1023/a:1012554328801. [DOI] [PubMed] [Google Scholar]
  • 64.Short SC, Traish D, Dowe A, Hines F, Gore M, Brada M. Thalidomide as an anti-angiogenic agent in relapsed gliomas. J Neurooncol. 2001;51:41–45. doi: 10.1023/a:1006414804835. [DOI] [PubMed] [Google Scholar]
  • 65.Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol. 2000;18:708–715. doi: 10.1200/JCO.2000.18.4.708. [DOI] [PubMed] [Google Scholar]
  • 66.Fine HA, Wen PY, Maher EA, et al. Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas. J Clin Oncol. 2003;21:2299–2304. doi: 10.1200/JCO.2003.08.045. [DOI] [PubMed] [Google Scholar]
  • 67.Baumann F, Bjeljac M, Kollias SS, et al. Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J Neurooncol. 2004;67:191–200. doi: 10.1023/b:neon.0000021803.01170.03. [DOI] [PubMed] [Google Scholar]
  • 68.Chang SM, Lamborn KR, Malec M, et al. Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2004;60:353–357. doi: 10.1016/j.ijrobp.2004.04.023. [DOI] [PubMed] [Google Scholar]
  • 69.Fine HA, Kim L, Albert PS, et al. A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors. Clin Cancer Res. 2007;13:7101–7106. doi: 10.1158/1078-0432.CCR-07-1546. [DOI] [PubMed] [Google Scholar]
  • 70.Drappatz J, Wong ET, Schiff D, et al. A pilot safety study of lenalidomide and radiotherapy for patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2009;73:222–227. doi: 10.1016/j.ijrobp.2008.03.046. [DOI] [PubMed] [Google Scholar]
  • 71.Buckner JC, Schomberg PJ, McGinnis WL, et al. A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer. 2001;92:420–433. doi: 10.1002/1097-0142(20010715)92:2<420::aid-cncr1338>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  • 72.Fine HA, Wen PY, Robertson M, et al. A phase I trial of a new recombinant human beta-interferon (BG9015) for the treatment of patients with recurrent gliomas. Clin Cancer Res. 1997;3:381–387. [PubMed] [Google Scholar]
  • 73.Grossman SA, Phuphanich S, Lesser G, et al. Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas. J Clin Oncol. 2001;19:3260–3266. doi: 10.1200/JCO.2001.19.13.3260. [DOI] [PubMed] [Google Scholar]
  • 74.Laterra JJ, Grossman SA, Carson KA, Lesser GJ, Hochberg FH, Gilbert MR. Suramin and radiotherapy in newly diagnosed glioblastoma: phase 2 NABTT CNS Consortium study. Neuro Oncol. 2004;6:15–20. doi: 10.1215/S1152851703000127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumongenesis. Cancer Lett. 2006;232:139–147. doi: 10.1016/j.canlet.2005.02.002. [DOI] [PubMed] [Google Scholar]
  • 76.Louis DN. Molecular pathology of malignant gliomas. Annu Rev Pathol. 2006;1:97–117. doi: 10.1146/annurev.pathol.1.110304.100043. [DOI] [PubMed] [Google Scholar]
  • 77.Raymond E, Brandes AA, Dittrich C, et al. Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol. 2008;26:4659–4665. doi: 10.1200/JCO.2008.16.9235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Wen PY, Yung WK, Lamborn KR, et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res. 2006;12:4899–4907. doi: 10.1158/1078-0432.CCR-06-0773. [DOI] [PubMed] [Google Scholar]
  • 79.Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005;16:1702–1708. doi: 10.1093/annonc/mdi317. [DOI] [PubMed] [Google Scholar]
  • 80.Reardon DA, Egorin MJ, Quinn JA, et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol. 2005;23:9359–9368. doi: 10.1200/JCO.2005.03.2185. [DOI] [PubMed] [Google Scholar]
  • 81.Desjardins A, Quinn JA, Vredenburgh JJ, et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol. 2007;83:53–60. doi: 10.1007/s11060-006-9302-2. [DOI] [PubMed] [Google Scholar]
  • 82.Dresemann G, Weller M, Bogdahn U, et al. Imatinib plus hydroxyurea versus hydroxyurea monotherapy in progressive glioblastoma: an international multi-center, open-label, randomized phase III study (Ambrosia-Study). Neuro Oncol 2008;Abstract MA19.
  • 83.Fine HA, Puduvalli VK, Chamberlain MC, et al. Enzastaurin (ENZ) versus lomustine (CCNU) in the treatment of recurrent, intracranial glioblastoma multiforme (GBM): A phase III study. J Clin Oncol 2008;26(May 20 Suppl):abstract 2005.
  • 84.Iniguez MA, Rodriguez A, Volpert OV, Fresno M, Redondo JM. Cyclooxygenase-2: a therapeutic target in angiogenesis. Trends Mol Med. 2003;9:73–78. doi: 10.1016/s1471-4914(02)00011-4. [DOI] [PubMed] [Google Scholar]
  • 85.Reardon DA, Quinn JA, Vredenburgh J, et al. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma. Cancer. 2005;103:329–338. doi: 10.1002/cncr.20776. [DOI] [PubMed] [Google Scholar]
  • 86.Levin VA, Giglio P, Puduvalli VK, et al. Combination chemotherapy with 13-cis-retinoic acid and celecoxib in the treatment of glioblastoma multiforme. J Neurooncol. 2006;78:85–90. doi: 10.1007/s11060-005-9062-4. [DOI] [PubMed] [Google Scholar]
  • 87.Schmidt NO, Westphal M, Hagel C, et al. 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;84:10–18. doi: 10.1002/(sici)1097-0215(19990219)84:1<10::aid-ijc3>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  • 88.Abounader R, Laterra J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol. 2005;7:436–451. doi: 10.1215/S1152851705000050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8:604–617. doi: 10.1038/nrc2353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Reardon DA, Fink KL, Mikkelsen T, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. 2008;26:5610–5617. doi: 10.1200/JCO.2008.16.7510. [DOI] [PubMed] [Google Scholar]
  • 91.Stupp R, Goldbrunner R, Neyns B, et al. Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol 2007;25, Part 1, No. 18S (June 20 Suppl): abstract 2000. [DOI] [PubMed]
  • 92.Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25:1651–1657. doi: 10.1200/JCO.2006.06.6514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Eskens FA, Dumez H, Hoekstra R, et al. Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of cilengitide (EMD 121974), a novel inhibitor of the integrins αvβ3 and αvβ5 in patients with advanced solid tumours. Eur J Cancer. 2003;39:917–926. doi: 10.1016/s0959-8049(03)00057-1. [DOI] [PubMed] [Google Scholar]
  • 94.Gilbert M, Lamborn K, Lassman A, et al. Tumor tissue delivery of cilengitide after intravenous administration to patients with recurrent glioblastoma (GBM): Preliminary data from NABTC protocol 03-02. Neuro Oncol. 2007;9:525–525. [Google Scholar]
  • 95.Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–436. doi: 10.1038/nrc1369. [DOI] [PubMed] [Google Scholar]
  • 96.Kim JT, Kim JS, Ko KW, et al. Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep. 2006;16:33–39. [PubMed] [Google Scholar]
  • 97.Herrlinger U, Rieger J, Steinbach JP, Nagele T, Dichgans J, Weller M. UKT-04 trial of continuous metronomic low-dose chemotherapy with methotrexate and cyclophosphamide for recurrent glioblastoma. J Neurooncol. 2005;71:295–299. doi: 10.1007/s11060-004-1726-y. [DOI] [PubMed] [Google Scholar]
  • 98.Tuettenberg J, Grobholz R, Korn T, Wenz F, Erber R, Vajkoczy P. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multi-forme. J Cancer Res Clin Oncol. 2005;131:31–40. doi: 10.1007/s00432-004-0620-5. [DOI] [PubMed] [Google Scholar]
  • 99.Kesari S, Schiff D, Doherty L, et al. Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults. Neuro Oncol. 2007;9:354–363. doi: 10.1215/15228517-2007-006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Perry JR, Mason WP, Belanger K, et al. The temozolomide RESCUE study: A phase II trial of continuous (28/28) dose-intense temozolomide (TMZ) after progression on conventional 5/28 day TMZ in patients with recurrent malignant glioma. J Clin Oncol 2008;26(May 20 Suppl):abstract 2010. [DOI] [PubMed]
  • 101.Strik HM, Buhk JH, Bock C, et al. Tegwondo: Development of a novel near-continuous dose-dense temozolomide regimen for the treatment of recurrent brain tumors. J Clin Oncol 2008;26(May 20 Suppl):abstract 13016.
  • 102.Bello L, Carrabba G, Giussani C, et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo. Cancer Res. 2001;61:7501–7506. [PubMed] [Google Scholar]
  • 103.Hegi ME, Liu L, Herman JG, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008;26:4189–4199. doi: 10.1200/JCO.2007.11.5964. [DOI] [PubMed] [Google Scholar]
  • 104.Quant EC, Norden AD, Drappatz J, et al. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol 2009;Mar 30 [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  • 105.Kerbel RS. Therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed. Cancer Cell. 2005;8:269–271. doi: 10.1016/j.ccr.2005.09.016. [DOI] [PubMed] [Google Scholar]
  • 106.Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogeuesis. Nat Rev Cancer. 2008;8:618–631. doi: 10.1038/nrc2444. [DOI] [PubMed] [Google Scholar]
  • 107.Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res. 2006;66:9054–9064. doi: 10.1158/0008-5472.CAN-05-3759. [DOI] [PubMed] [Google Scholar]
  • 108.Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206–220. doi: 10.1016/j.ccr.2008.01.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Rubenstein JL, Kim J, Ozawa T, et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia. 2000;2:306–314. doi: 10.1038/sj.neo.7900102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Kunkel P, Ulbricht U, Bohlen P, et al. 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;61:6624–6628. [PubMed] [Google Scholar]
  • 111.Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–231. doi: 10.1016/j.ccr.2009.01.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG. Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–239. doi: 10.1016/j.ccr.2009.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–969. [PubMed] [Google Scholar]
  • 114.Carlson MR, Pope WB, Horvath S, et al. Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2. Clin Cancer Res. 2007;13:2592–2598. doi: 10.1158/1078-0432.CCR-06-2772. [DOI] [PubMed] [Google Scholar]
  • 115.Kamoun WS, Ley CD, Farrar CT, et al. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted ldnase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 2009 Mar 30 [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  • 116.Hylton N. Dynamic contrast-enhanced magnetic resonance imaging as an imaging biomarker. J Clin Oncol. 2006;24:3293–3298. doi: 10.1200/JCO.2006.06.8080. [DOI] [PubMed] [Google Scholar]
  • 117.Barrett T, Brechbiel M, Bernardo M, Choyke PL. MRI of tumor angiogenesis. J Magn Reson Imaging. 2007;26:235–249. doi: 10.1002/jmri.20991. [DOI] [PubMed] [Google Scholar]
  • 118.Pöpperl G, Kreth FW, Herms J, et al. Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods? [Erratum in: J Nucl Med 2006;47:806] J Nucl Med. 2006;47:393–403. [PubMed] [Google Scholar]
  • 119.Provenzale JM. Imaging of angiogenesis: clinical techniques and novel imaging methods. AJR Am J Roentgenol. 2007;188:11–23. doi: 10.2214/AJR.06.0280. [DOI] [PubMed] [Google Scholar]
  • 120.Sathornsumetee S, Cao Y, Marcello JE, et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol. 2008;26:271–278. doi: 10.1200/JCO.2007.13.3652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Willett CG, Boucher Y, Duda DG, et al. 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;23:8136–8139. doi: 10.1200/JCO.2005.02.5635. [DOI] [PubMed] [Google Scholar]
  • 122.Wen PY, Schiff D, Kesari S, Drappatz J, Gigas DC, Doherty L. Medical management of patients with brain tumors. J Neurooncol. 2006;80:313–332. doi: 10.1007/s11060-006-9193-2. [DOI] [PubMed] [Google Scholar]
  • 123.Lai A, Filka E, McGibbon B, et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys. 2008;71:1372–1380. doi: 10.1016/j.ijrobp.2007.11.068. [DOI] [PubMed] [Google Scholar]
  • 124.Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006;42:3127–3139. doi: 10.1016/j.ejca.2006.09.015. [DOI] [PubMed] [Google Scholar]
  • 125.Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7:475–485. doi: 10.1038/nrc2152. [DOI] [PubMed] [Google Scholar]
  • 126.Narayana A, Golfinos JG, Fischer I, et al. Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. Int J Radiat Oncol Biol Phys. 2008;72:383–389. doi: 10.1016/j.ijrobp.2008.05.062. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES