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The Complexities of Resistance to Bevacizumab

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DOI: 10.4236/jct.2012.35064    3,934 Downloads   6,788 Views   Citations


Glioblastoma is a highly malignant primary tumor of the central nervous system tumor with a poor survival rate. The treatment of glioblastoma is shifting from a purely cytotoxic approach to one that incorporates anti-angiogenic agents. Bevacizumab (Avastin; Roche) was approved in the United States for the treatment of recurrent glioblastoma in May 2009 and showed encouraging results. However, “rebound” tumor progression with accelerated clinical decline has been observed after cessation of bevacizumab therapy in patients with high-grade gliomas and there is no effective treatment for the recurrent glioblastoma after bevacizumab failure. This review summarizes the characteristics of glioblastoma as well as the possible mechanisms of recurrence after anti-angiogenic therapy. Furthermore, alterations of the key molecular pathways and glycometabolic remodeling in glioblastoma are also discussed within. A better understanding of the complexities underpinning the resistance to bevacizumab and the combination of targeting cancer metabolism and anti-VEGF therapy may ultimately result in new modes of treatment, which hopefully improve the overall survival for patients diagnosed with glioblastoma.

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The authors declare no conflicts of interest.

Cite this paper

H. Shen and K. McDonald, "The Complexities of Resistance to Bevacizumab," Journal of Cancer Therapy, Vol. 3 No. 5, 2012, pp. 491-503. doi: 10.4236/jct.2012.35064.


[1] CBTRUS, “2011 CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2007,” Central Brain Tumor Registry of the United State, 2011.
[2] D. N. Louis, H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, B. W. Scheithauer and P. Kleihues, “The 2007 WHO Classification of Tumours of the Central Nervous System,” Acta Neuropathologica, Vol. 114, No. 2, 2007, pp. 97-109. doi:10.1007/s00401-007-0243-4
[3] M. D. Walker, E. Alexander Jr., W. E. Hunt, C. S. Maccarty, M. S. Mahaley Jr., J. Mealey Jr., H. A. Norrell, G. Owens, J. Ransohoff, C. B. Wilson, E. A. Gehan and T. A. Strike, “Evaluation of BCNU and/or Radiotherapy in the Treatment of Anaplastic Gliomas. A Cooperative Clinical trial,” Journal of Neurosurgery, Vol. 49, No. 3, 1978, pp. 333-343. doi:10.3171/jns.1978.49.3.0333
[4] M. D. Walker, T. A. Strike and G. E. Sheline, “An Analysis of Dose-Effect Relationship in the Radiotherapy of Malignant Gliomas,” International Journal of Radiation Oncology, Biology, Physics, Vol. 5, No. 10, 1979, pp. 1725-1731. doi:10.1016/0360-3016(79)90553-4
[5] M. D. Walker, S. B. Green, D. P. Byar, E. Alexander Jr., U. Batzdorf, W. H. Brooks, W. E. Hunt, C. S. Maccarty, M. S. Mahaley Jr., J. Mealey Jr., G. Owens, J. Ransohoff, J. T. Robertson, W. R. Shapiro, K. R. Smith Jr., C. B. Wilson and T. A. Strike, “Randomized Comparisons of Radiotherapy and Nitrosoureas for the Treatment of Malignant Glioma after Surgery,” The New England Journal of Medicine, Vol. 303, No. 23, 1980, pp. 1323-1329. doi:10.1056/NEJM198012043032303
[6] R. Stupp, W. P. Mason, M. J. Van Den Bent, M. Weller, B. Fisher, M. J. Taphoorn, K. Belanger, A. A. Brandes, C. Marosi, U. Bogdahn, J. Curschmann, R. C. Janzer, S. K. Ludwin, T. Gorlia, A. Allgeier, D. Lacombe, J. G. Cairncross, E. Eisenhauer and R. O. Mirimanoff, “Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma,” The New England Journal of Medicine, Vol. 352, No. 10, 2005, pp. 987-996.doi:10.1056/NEJMoa043330
[7] L. A. Stewart, “Chemotherapy in Adult High-Grade Glioma: A Systematic Review and Meta-Analysis of Individual Patient Data from 12 Randomised Trials,” The Lancet, Vol. 359, No. 9311, 2002, pp. 1011-1018.doi:10.1016/S0140-6736(02)08091-1
[8] R. L. Engerman, D. Pfaffenbach and M. D. Davis, “Cell Turnover of Capillaries,” Laboratory Investigation, Vol. 17, No. 6, 1967, pp. 738-743.
[9] B. Hobson and J. Denekamp, “Endothelial Proliferation in Tumours and Normal Tissues: Continuous Labelling Studies,” British Journal of Cancer, Vol. 49, No. 4, 1984, pp. 405-413. doi:10.1038/bjc.1984.66
[10] P. Carmeliet, “Angiogenesis in Life, Disease and Medicine,” Nature, Vol. 438, No. 7070, 2005, pp. 932-936. doi:10.1038/nature04478
[11] J. Folkman, “Tumor Angiogenesis: Therapeutic Implications,” The New England Journal of Medicine, Vol. 285, No. 21, 1971, pp. 1182-1186. doi:10.1056/NEJM197111182852108
[12] R. K. Jain, E. Di Tomaso, D. G. Duda, J. S. Loeffler, A. G. Sorensen and T. T. Batchelor, “Angiogenesis in Brain Tumours,” Nature Reviews Neuroscience, Vol. 8, No. 8, 2007, pp. 610-622. doi:10.1038/nrn2175
[13] B. Kaur, F. W. Khwaja, E. A. Severson, S. L. Matheny, D. J. Brat and E. G. Van Meir, “Hypoxia and the Hypoxia-Inducible-Factor Pathway in Glioma Growth and Angiogenesis,” Neuro-Oncology, Vol. 7, No. 2, 2005, pp. 134-153. doi:10.1215/S1152851704001115
[14] S. P. Leon, R. D. Folkerth and P. M. Black, “Microvessel Density is a Prognostic Indicator for Patients with Astroglial Brain Tumors,” Cancer, Vol. 77, No. 2, 1996, pp. 362-372.doi:10.1002/(SICI)1097-0142(19960115)77:2<362::AID-CNCR20>3.0.CO;2-Z
[15] N. O. Schmidt, M. Westphal, C. Hagel, S. Ergun, D. Stavrou, E. M. Rosen and K. Lamszus, “Levels of Vascular Endothelial Growth Factor, Hepatocyte Growth Factor/Scatter Factor and Basic Fibroblast Growth Factor in Human Gliomas and Their Relation to Angiogenesis,” International Journal of Cancer, Vol. 84, No. 1, 1999, pp. 10-18.doi:10.1002/(SICI)1097-0215(19990219)84:1<10::AID-IJC3>3.0.CO;2-L
[16] Y. H. Zhou, F. Tan, K. R. Hess and W. K. Yung, “The Expression of PAX6, PTEN, Vascular Endothelial Growth Factor, and Epidermal Growth Factor Receptor in Gliomas: Relationship to Tumor Grade and Survival,” Clinical Cancer Research, Vol. 9, No. 9, 2003, pp. 3369-3375.
[17] M. Saleh, K. Vasilopoulos, S. S. Stylli, A. H. Kaye and A. F. Wilks, “The Expression of Antisense Vascular Endothelial Growth Factor (VEGF) Sequences Inhibits Intracranial C6 Glioma Growth in Vivo by Suppressing Tumour Angiogenesis,” Journal of Clinical Neuroscience, Vol. 3, No. 4, 1996, pp. 366-372. doi:10.1016/S0967-5868(96)90035-1
[18] B. A. Reynolds and S. Weiss, “Generation of Neurons and Astrocytes from Isolated Cells of the Adult Mammalian Central Nervous System,” Science, Vol. 255, No. 5052, 1992, pp. 1707-1710. doi:10.1126/science.1553558
[19] N. Sanai, A. Alvarez-Buylla and M. S. Berger, “Neural Stem Cells and the Origin of Gliomas,” The New England Journal of Medicine, Vol. 353, No. 8, 2005, pp. 811-822. doi:10.1056/NEJMra043666
[20] S. K. Singh, C. Hawkins, I. D. Clarke, J. A. Squire, J. Bayani, T. Hide, R. M. Henkelman, M. D. Cusimano and P. B. Dirks, “Identification of Human Brain Tumour Initiating Cells,” Nature, Vol. 432, No. 7015, 2004, pp. 396-401. doi:10.1038/nature03128
[21] P. B. Dirks, “Brain Tumor Stem Cells: Bringing Order to the Chaos of Brain Cancer,” Journal of Clinical Neuroscience, Vol. 26, No. 17, 2008, pp. 2916-2924. doi:10.1200/JCO.2008.17.6792
[22] S. Bao, Q. Wu, R. E. Mclendon, Y. Hao, Q. Shi, A. B. Hjelmeland, M. W. Dewhirst, D. D. Bigner and J. N. Rich, “Glioma Stem Cells Promote Radioresistance by Preferential Activation of the DNA Damage Response,” Nature, Vol. 444, No. 7120, 2006, pp. 756-760. doi:10.1038/nature05236
[23] G. Liu, X. Yuan, Z. Zeng, P. Tunici, H. Ng, I. R. Abdulkadir, L. Lu, D. Irvin, K. L. Black and J. S. Yu, “Analysis of Gene Expression and Chemoresistance of CD133+ Cancer Stem Cells in Glioblastoma,” Molecular Cancer, Vol. 5, 2006, p. 67 doi:10.1186/1476-4598-5-67
[24] A. Salmaggi, A. Boiardi, M. Gelati, A. Russo, C. Calatozzolo, E. Ciusani, F. L. Sciacca, A. Ottolina, E. A. Parati, C. La Porta, G. Alessandri, C. Marras, D. Croci and M. De Rossi, “Glioblastoma-Derived Tumorospheres Identify a Population of Tumor Stem-Like Cells with Angiogenic Potential and Enhanced Multidrug Resistance Phenotype,” Glia, Vol. 54, No. 8, 2006, pp. 850-860. doi:10.1002/glia.20414
[25] M. Dean, T. Fojo and S. Bates, “Tumour Stem Cells and Drug Resistance,” Nature Reviews Cancer, Vol. 5, No. 4, 2005, pp. 275-284. doi:10.1038/nrc1590
[26] S. Bao, Q. Wu, S. Sathornsumetee, Y. Hao, Z. Li, A. B. Hjelmeland, Q. Shi, R. E. Mclendon, D. D. Bigner and J. N. Rich, “Stem Cell-Like Glioma Cells Promote Tumor Angiogenesis through Vascular Endothelial Growth Factor,” Cancer Research, Vol. 66, No. 16, 2006, pp. 7843-7848. doi:10.1158/0008-5472.CAN-06-1010
[27] C. Folkins, Y. Shaked, S. Man, T. Tang, C. R. Lee, Z. Zhu, R. M. Hoffman and R. S. Kerbel, “Glioma Tumor Stem-Like Cells Promote Tumor Angiogenesis and Vasculogenesis via Vascular Endothelial Growth Factor and Stromal-Derived Factor 1,” Cancer Reseaarch, Vol. 69, No. 18, 2009, pp. 7243-7251.doi:10.1158/0008-5472.CAN-09-0167
[28] N. Oka, A. Soeda, A. Inagaki, M. Onodera, H. Maruyama, A. Hara, T. Kunisada, H. Mori and T. Iwama, “VEGF Promotes Tumorigenesis and Angiogenesis of Human Glioblastoma Stem Cells,” Biochemical and Biophysical Research Communications, Vol. 360, No. 3, 2007, pp. 553-559. doi:10.1016/j.bbrc.2007.06.094
[29] L. G. Presta, H. Chen, S. J. O’connor, V. Chisholm, Y. G. Meng, L. Krummen, M. Winkler and N. Ferrara, “Humanization of an Anti-Vascular Endothelial Growth Factor Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders,” Cancer Research, Vol. 57, No. 20, 1997, pp. 4593-4599.
[30] N. Ferrara, K. J. Hillan, H. P. Gerber and W. Novotny, “Discovery and Development of Bevacizumab, an Anti-VEGF Antibody for Treating Cancer,” Nature Reviews Drug Discovery, Vol. 3, No. 5, 2004, pp. 391-400 doi:10.1038/nrd1381
[31] M. H. Cohen, Y. L. Shen, P. Keegan and R. Pazdur, “FDA Drug Approval Summary: Bevacizumab (Avastin) as Treatment of Recurrent Glioblastoma Multiforme,” The Oncologist, Vol. 14, No. 11, 2009, pp. 1131-1138.doi:10.1634/theoncologist.2009-0121
[32] J. J. Vredenburgh, A. Desjardins, J. E. Herndon, J. Marcello, D. A. Reardon, J. A. Quinn, J. N. Rich, S. Sathornsumetee, S. Gururangan, J. Sampson, M. Wagner, L. Bailey, D. D. Bigner, A. H. Friedman and H. S. Friedman, “Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme,” Journal of Clinical Oncology, Vol. 25, No. 30, 2007, pp. 4722-4729. doi:10.1200/JCO.2007.12.2440
[33] H. S. Friedman, M. D. Prados, P. Y. Wen, T. Mikkelsen, D. Schiff, L. E. Abrey, W. K. Yung, N. Paleologos, M. K. Nicholas, R. Jensen, J. Vredenburgh, J. Huang, M. Zheng and T. Cloughesy, “Bevacizumab alone and in Combination with Irinotecan in Recurrent Glioblastoma,” Journal of Clinical Oncology, Vol. 27, No. 28, 2009, pp. 4733-4740. doi:10.1200/JCO.2008.19.8721
[34] W. Wick, M. Weller, M. Van Den Bent and R. Stupp, “Bevacizumab and Recurrent Malignant Gliomas: A European Perspective,” Journal of Clinical Oncology, Vol. 28, No. 12, 2010, pp. e188-e189. doi:10.1200/JCO.2009.26.9027
[35] D. A. Reardon, A. Desjardins, K. B. Peters, S. Gururangan, J. H. Sampson, R. E. Mclendon, J. E. Herndon,A. Bulusu, S. Threatt, A. H. Friedman, J. J. Vredenburgh and H. S. Friedman, “Phase II Study of Carboplatin, Irinotecan, and Bevacizumab for Bevacizumab Naive, Recurrent Glioblastoma,” Journal of Neurooncology, Vol. 107, No. 1, 2012, pp. 155-164. doi:10.1007/s11060-011-0722-2
[36] D. A. Reardon, A. Desjardins, K. B. Peters, J. J. Vredenburgh, S. Gururangan, J. H. Sampson, R. E. Mclendon, J. E. Herndon, A. Coan, S. Threatt, A. H. Friedman and H. S. Friedman, “Phase 2 Study of Carboplatin, Irinotecan, and Bevacizumab for Recurrent Glioblastoma after Progression on Bevacizumab Therapy,” Cancer, Vol. 117, No. 23, 2011, pp. 5351-5358. doi:10.1002/cncr.26188
[37] D. A. Reardon,A. Desjardins,K. Peters,S. Gururangan, J. Sampson, J. N. Rich, R. Mclendon, J. E. Herndon, J. Marcello, S. Threatt, A. H. Friedman, J. J. Vredenburgh and H. S. Friedman, “Phase II Study of Metronomic Chemotherapy with Bevacizumab for Recurrent Glioblastoma after Progression on Bevacizumab Therapy,” Journal of Neurooncology, Vol. 103, No. 2, 2011, pp. 371-379. doi:10.1007/s11060-010-0403-6
[38] A. Desjardins, D. A. Reardon, A. Coan, J. Marcello, J. E. Herndon, L. Bailey, K. B. Peters, H. S. Friedman and J. J. Vredenburgh, “Bevacizumab and Daily Temozolomide for Recurrent Glioblastoma,” Cancer, Vol. 118, No. 5, 2011, pp. 1302-1312. doi:10.1002/cncr.26381
[39] D. A. Reardon, A. Desjardins, J. J. Vredenburgh, S. Gururangan, J. H. Sampson, S. Sathornsumetee, R. E. Mclendon, J. E. Herndon, J. E. Marcello, J. Norfleet, A. H. Friedman, D. D. Bigner and H. S. Friedman, “Metronomic Chemotherapy with Daily, Oral Etoposide Plus Bevacizumab for Recurrent Malignant Glioma: A Phase II Study,” British Journal of Cancer, Vol. 101, No. 12, 2009, pp. 1986-1994. doi:10.1038/sj.bjc.6605412
[40] S. Sathornsumetee, A. Desjardins, J. J. Vredenburgh, R. E. Mclendon, J. Marcello, J. E. Herndon, A. Mathe, M. Hamilton, J. N. Rich, J. A. Norfleet, S. Gururangan, H. S. Friedman and D. A. Reardon, “Phase II Trial of Bevacizumab and Erlotinib in Patients with Recurrent Malignant Glioma,” Neuro-Oncology, Vol. 12, No. 12, 2010, pp. 1300-1310. doi:10.1093/neuonc/noq099
[41] B. Hasselbalch, U. Lassen, S. Hansen, M. Holmberg, M. Sorensen, M. Kosteljanetz, H. Broholm, M. T. Stockhausen and H. S. Poulsen, “Cetuximab, Bevacizumab, and Irinotecan for Patients with Primary Glioblastoma and Progression after Radiation Therapy and Temozolomide: A Phase II Trial,” Neuro-Oncology, Vol. 12, No. 5, 2010, pp. 508-516. doi:10.1093/neuonc/nop063
[42] V. Stark-Vance, “Bevacizumab and CPT-11 in the Treatment of Relapsed Maliganant Glioma,” Neuro-Oncology, Vol. 369, No. 7, 2005, Abstract 342.
[43] W. B. Pope, A. Lai, P. Nghiemphu, P. Mischel and T. F. Cloughesy, “MRI in Patients with High-Grade Gliomas Treated with Bevacizumab and Chemotherapy,” Neurology, Vol. 66, No. 8, 2006, pp. 1258-1260. doi:10.1212/01.wnl.0000250628.10420.d8
[44] J. J. Vredenburgh, A. Desjardins, J. E. Herndon, J. M. Dowell, D. A. Reardon, J. A. Quinn, J. N. Rich, S. Sathornsumetee, S. Gururangan, M. Wagner, D. D. Bigner, A. H. Friedman and H. S. Friedman, “Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma,” Clinical Cancer Research, Vol. 13, No. 4, 2007, pp. 1253-1259. doi:10.1158/1078-0432.CCR-06-2309
[45] A. D. Norden, G. S. Young, K. Setayesh, A. Muzikansky, R. Klufas, G. L. Ross, A. S. Ciampa, L. G. Ebbeling, B. Levy, J. Drappatz, S. Kesari and P. Y. Wen, “Bevacizumab for Recurrent Malignant Gliomas: Efficacy, Toxicity, and Patterns of Recurrence,” Neurology, Vol. 70, No. 10, 2008, pp. 779-787. doi:10.1212/01.wnl.0000339387.03225.0a
[46] A. Narayana, P. Kelly, J. Golfinos, E. Parker, G. Johnson, E. Knopp, D. Zagzag, I. Fischer, S. Raza, P. Medabalmi, P. Eagan and M. L. Gruber, “Antiangiogenic Therapy Using Bevacizumab in Recurrent High-Grade Glioma: Impact on Local Control and Patient Survival,” Journal of Neurosurgery, Vol. 110, No. 1, 2009, pp. 173-180 doi:10.3171/2008.4.17492
[47] P. L. Nghiemphu, W. Liu, Y. Lee, T. Than, C. Graham, A. Lai, R. M. Green, W. B. Pope, L. M. Liau, P. S. Mischel, S. F. Nelson, R. Elashoff and T. F. Cloughesy, “Bevacizumab and Chemotherapy for Recurrent Glioblastoma: A Single-Institution Experience,” Neurology, Vol. 72, No. 14, 2009, pp. 1217-1222. doi:10.1212/01.wnl.0000345668.03039.90
[48] H. S. Poulsen, K. Grunnet, M. Sorensen, P. Olsen, B. Hasselbalch, K. Nelausen, M. Kosteljanetz and U. Lassen, “Bevacizumab Plusirinotecan in the Treatment Patients with Progressive Recurrent Malignant Brain Tumours,” Acta Oncology, Vol. 48, No. 1, 2009, pp. 52-58. doi:10.1080/02841860802537924
[49] R. M. Zuniga, R. Torcuator, R. Jain, J. Anderson, T. Doyle, S. Ellika, L. Schultz and T. Mikkelsen, “Efficacy, Safety and Patterns of Response and Recurrence in Patients with Recurrent High-Grade Gliomas Treated with Bevacizumab Plus Irinotecan,” Journal of Neurooncology, Vol. 91, No. 3, 2009, pp. 329-336. doi:10.1007/s11060-008-9718-y
[50] M. R. Gilbert, “RTOG 0625: A Phase II Study of Bevacizumab with Irinotecan in Recurrent Glioblastoma (GBM) [Abstract],” Journal of Clinical Oncology, Vol. 27, Suppl. 15, 2009, Abstract 2011.
[51] P. H. Gutin, F. M. Iwamoto, K. Beal, N. A. Mohile, S. Karimi, B. L. Hou, S. Lymberis, Y. Yamada, J. Chang and L. E. Abrey, “Safety and Efficacy of Bevacizumab with Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas,” International Journal of Radiation Oncology, Biology, Physics, Vol. 75, No. 1, 2009, pp. 156-163. doi:10.1016/j.ijrobp.2008.10.043
[52] T. N. Kreisl, L. Kim, K. Moore, P. Duic, C. Royce, I. Stroud, N. Garren, M. Mackey, J. A. Butman, K. Camphausen, J. Park, P. S. Albert and H. A. Fine, “Phase II trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma,” Journal of Clinical Oncology, Vol.27, No. 5, 2009, pp. 740-745. doi:10.1200/JCO.2008.16.3055
[53] M. C. Chamberlain and S. K. Johnston, “Salvage Therapy with Single Agent Bevacizumab for Recurrent Glioblastoma,” Journal of Neurooncology, Vol. 96, No. 2, 2010, pp. 259-269. doi:10.1007/s11060-009-9957-6
[54] J. J. Raizer, S. Grimm, M. C. Chamberlain, M. K. Nicholas, J. P. Chandler, K. Muro, S. Dubner, A. W. Rademaker, J. Renfrow and M. Bredel, “A Phase 2 Trial of Single-Agent Bevacizumab Given in an Every-3-Week Schedule for Patients with Recurrent High-Grade Gliomas,” Cancer, Vol. 116, No. 22, 2010, pp. 5297-5305. doi:10.1002/cncr.25462
[55] L. M. Ellis and D. J. Hicklin, “Pathways Mediating Resistance to Vascular Endothelial Growth Factor-Targeted Therapy,” Clinical Cancer Research, Vol. 14, No. 20, 2008, pp. 6371-6375. doi:10.1158/1078-0432.CCR-07-5287
[56] E. Hattingen, A. Jurcoane, O. Bahr, J. Rieger, J. Mager- kurth, S. Anti, J. P. Steinbach and U. Pilatus, “Bevacizumab Impairs Oxidative Energy Metabolism and Shows Antitumoral Effects in Recurrent Glioblastomas: A 31P/1H MRSI and Quantitative Magnetic Resonance Imaging Study,” Neuro-Oncology, Vol. 13, No. 12, 2011, pp. 1349-1363. doi:10.1093/neuonc/nor132
[57] R. K. Jain, “Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy,” Science, Vol. 307, No. 5706, 2005, pp. 58-62. doi:10.1126/science.1104819
[58] O. Keunen, M. Johansson, A. Oudin, M. Sanzey, S. A. Rahim, F. Fack, F. Thorsen, T. Taxt, M. Bartos, R. Jirik, H. Miletic, J. Wang, D. Stieber, L. Stuhr, I. Moen, C. B. Rygh, R. Bjerkvig and S. P. Niclou, “Anti-VEGF treatment Reduces Blood Supply and Increases Tumor Cell Invasion in Glioblastoma,” Proceedings of the National Academy Sciences of the United States of America, Vol. 108, No. 9, 2011, pp. 3749-3754. doi:10.1073/pnas.1014480108
[59] J. Ma, S. Pulfer, S. Li, J. Chu, K. Reed and J. M. Gallo, “Pharmacodynamic-Mediated Reduction of Temozolomide Tumor Concentrations by the Angiogenesis Inhibitor TNP-470,” Cancer Research, Vol. 61, No. 14, 2001, pp. 5491-5498.
[60] R. Murata, Y. Nishimura and M. Hiraoka, “An Antiangiogenic Agent (TNP-470) Inhibited Reoxygenation during Fractionated Radiotherapy of Murine Mammary Carcinoma,” International Journal of Radiation Oncology, Biology, Physics, Vol. 37, No. 5, 1997, pp. 1107-1113.doi:10.1016/S0360-3016(96)00628-1
[61] B. M. Fenton, S. F. Paoni and I. Ding, “Effect of VEGF Receptor-2 Antibody on Vascular Function and Oxygenation in Spontaneous and Transplanted Tumors,” Radiotherapy & Oncology, Vol. 72, No. 2, 2004, pp. 221-230. doi:10.1016/j.radonc.2004.05.005
[62] A. A. Van Der Veldt, M. Lubberink, I. Bahce, M. Walraven, M. P. De Boer, H. N. Greuter, N. H. Hendrikse, J. Eriksson, A. D. Windhorst, P. E. Postmus, H. M. Verheul, E. H. Serne, A. A. Lammertsma and E. F. Smit, “Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs,” Cancer Cell, Vol. 21, No. 1, 2012, pp. 82-91. doi:10.1016/j.ccr.2011.11.023
[63] O. Casanovas, D. J. Hicklin, G. Bergers and D. Hanahan, “Drug Resistance by Evasion of Antiangiogenic Targeting of VEGF Signaling in Late-Stage Pancreatic Islet Tumors,” Cancer Cell, Vol. 8, No. 4, 2005, pp. 299-309. doi:10.1016/j.ccr.2005.09.005
[64] A. K. Lucio-Eterovic, Y. Piao and J. F. De Groot, “Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy,” Clinical Cancer Research, Vol. 15, No. 14, 2009, pp. 4589- 4599. doi:10.1158/1078-0432.CCR-09-0575
[65] R. K. Jain, D. G. Duda, J. W. Clark and J. S. Loeffler, “Lessons from Phase III Clinical Trials on Anti-VEGF Therapy for Cancer,” Nature Clinical Practice Oncology, Vol. 3, No. 1, 2006, pp. 24-40. doi:10.1038/ncponc0403
[66] W. B. Nagengast, M. N. Lub-De Hooge, S. F. Oosting, W. F. Den Dunnen, F. J. Warnders, A. H. Brouwers, J. R. De Jong, P. M. Price, H. Hollema, G. A. Hospers, P. H. Elsinga, J. W. Hesselink, J. A. Gietema and E. G. De Vries, “VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment,” Cancer Research, Vol. 71, No. 1, 2011, pp. 143-153. doi:10.1158/0008-5472.CAN-10-1088
[67] P. Carmeliet and R. K. Jain, “Molecular Mechanisms and Clinical Applications of Angiogenesis,” Nature, Vol. 473, No. 7347, 2011, pp. 298-307. doi:10.1038/nature10144
[68] M. Franco, P. Roswall, E. Cortez, D. Hanahan and K. Pietras, “Pericytes Promote Endothelial Cell Survival through Induction of Autocrine VEGF-A Signaling and Bcl-w Expression,” Blood, Vol. 118, No. 10, 2011, pp. 2906-2917. doi:10.1182/blood-2011-01-331694
[69] N. Ferrara, “Pathways Mediating VEGF-Independent Tumor Angiogenesis,” Cytokine Growth Factor Reviews, Vol. 21, No. 1, 2010, pp. 21-26. doi:10.1016/j.cytogfr.2009.11.003
[70] S. Song, A. J. Ewald, W. Stallcup, Z. Werb and G. Bergers, “PDGFR Beta+ Perivascular Progenitor Cells in Tumours Regulate Pericyte Differentiation and Vascular Survival,” Nature Clinical Practice Oncology, Vol. 7, No. 9, 2005, pp. 870-879. doi:10.1038/ncb1288
[71] S. Pennacchietti, P. Michieli, M. Galluzzo, M. Mazzone, S. Giordano and P. M. Comoglio, “Hypoxia Promotes Invasive Growth by Transcriptional Activation of the Met Protooncogene,” Cancer Cell, Vol. 3, No. 4, 2003, pp. 347-361. doi:10.1016/S1535-6108(03)00085-0
[72] C. Birchmeier and E. Gherardi, “Developmental Roles of HGF/SF and Its Receptor, the c-Met Tyrosine Kinase,” Trends in Cell Biology, Vol. 8, No. 10, 1998, pp. 404-410. doi:10.1016/S0962-8924(98)01359-2
[73] T. Nakamura, S. Mizuno, K. Matsumoto, Y. Sawa and H. Matsuda, “Myocardial Protection from Is Chemia/Reperfusion Injury by Endogenous and Exogenous HGF,” Journal of Clinical Investigation, Vol. 106, No. 12, 2000, pp. 1511-1519. doi:10.1172/JCI10226
[74] C. G. Huh, V. M. Factor, A. Sanchez, K. Uchida, E. A. Conner and S. S. Thorgeirsson, “Hepatocyte Growth Factor/c-Met Signaling Pathway is Required for Efficient Liver Regeneration and Repair,” Proceedings of the National Academy Sciences of the United States of America, Vol. 101, No. 13, 2004, pp. 4477-4482. doi:10.1073/pnas.0306068101
[75] P. Kunkel, S. Muller, P. Schirmacher, D. Stavrou, R. Fillbrandt, M. Westphal and K. Lamszus, “Expression and Localization of Scatter Factor/Hepatocyte Growth Factor in Human Astrocytomas,” Neuro-Oncology, Vol. 3, No. 2, 2001, pp. 82-88. doi:10.1093/neuonc/3.2.82
[76] S. Koochekpour, M. Jeffers, S. Rulong, G. Taylor, E. Klineberg, E. A. Hudson, J. H. Resau and G. F. Vande Woude, “Met and Hepatocyte Growth Factor/Scatter Factor Expression in Human Gliomas,” Cancer Research, Vol. 57, No. 23, 1997, pp. 5391-5398.
[77] T. Martens, N. O. Schmidt, C. Eckerich, R. Fillbrandt, M. Merchant, R. Schwall, M. Westphal and K. Lamszus, “A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth in Vivo,” Clinical Cancer Research, Vol. 12, No. 20, 2006, pp. 6144-6152. doi:10.1158/1078-0432.CCR-05-1418
[78] Genentech, “A Study of the Safety and Pharmacology of MetMAb (PRO143966), a Monovalent Antagonist Antibody to the Receptor C-Met, Administered Intravenously in Patients with Locally Advanced or Metastatic Solid Tumors,” 2010.
[79] Pfizer, “A Study of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, in Patients with Advanced Cancer,” 2007-2012.
[80] P. Y. Wen, D. Schiff, T. F. Cloughesy, J. J. Raizer, J. Laterra, M. Smitt, M. Wolf, K. S. Oliner, A. Anderson, M. Zhu, E. Loh and D. A. Reardon, “A Phase II Study Evaluating the Efficacy and Safety of AMG 102 (Rilotumumab) in Patients with Recurrent Glioblastoma,” Neuro-Oncology, Vol. 13, No. 4, 2011, pp. 437-446. doi:10.1093/neuonc/noq198
[81] D. University, “AMG 102 and Avastin for Recurrent Malignant Glioma,” 2010-2012.
[82] T. T. Batchelor, A. G. Sorensen, E. Di Tomaso, W. T. Zhang, D. G. Duda, K. S. Cohen, K. R. Kozak, D. P. Cahill, P. J. Chen, M. Zhu, M. Ancukiewicz, M. M. Mrugala, S. Plotkin, J. Drappatz, D. N. Louis, P. Ivy, D. T. Scadden, T. Benner, J. S. Loeffler, P. Y. Wen and R. K. Jain, “AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients,” Cancer Cell, Vol. 11, No. 1, 2007, pp. 83-95. doi:10.1016/j.ccr.2006.11.021
[83] M. Relf, S. Lejeune, P. A. Scott, S. Fox, K. Smith, R. Leek, A. Moghaddam, R. Whitehouse, R. Bicknell and A. L. Harris, “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 Research, Vol. 57, No. 5, 1997, pp. 963-969.
[84] R. Rahman, S. Smith, C. Rahman, and R. Grundy, "Antiangiogenic therapy and mechanisms of tumor resistance in malignant glioma." J Oncol. Vol. 2010, No. 2010, pp. 251231 doi:10.1155/2010/251231
[85] J. M. Heddleston, Z. Li, R. E. Mclendon, A. B. Hjelmeland and J. N. Rich, “The Hypoxic Microenvironment Maintains Glioblastoma Stem Cells and Promotes Reprogramming towards a Cancer Stem Cell Phenotype,” Cell Cycle, Vol. 8, No. 20, 2009, pp. 3274-3284.doi:10.4161/cc.8.20.9701
[86] A. Soeda, M. Park, D. Lee, A. Mintz, A. Androutsellis-Theotokis, R. D. Mckay, J. Engh, T. Iwama, T. Kunisada, A. B. Kassam, I. F. Pollack and D. M. Park, “Hypoxia Promotes Expansion of the CD133-Positive Glioma Stem Cells through Activation of HIF-1 Alpha,” Oncogene, Vol. 28, No. 45, 2009, pp. 3949-3959. doi:10.1038/onc.2009.252
[87] G. L. Semenza, “HIF-1 and Tumor Progression: Pathophysiology and Therapeutics,” Trends in Molecular Medicine, Vol. 8, No. 4, 2002, pp. S62-S67. doi:10.1016/S1471-4914(02)02317-1
[88] D. P. Brazil, J. Park and B. A. Hemmings, “PKB Binding Proteins. Getting in on the Akt,” Cell, Vol. 111, No. 3, 2002, pp. 293-303. doi:10.1016/S0092-8674(02)01083-8
[89] I. Galetic, M. Andjelkovic, R. Meier, D. Brodbeck, J. Park and B. A. Hemmings, “Mechanism of Protein Kinase B Activation by Insulin/Insulin-Like Growth Factor-1 Revealed by Specific Inhibitors of Phosphoinositide 3-Kinase-Significance for Diabetes and Cancer,” Pharmacology & Therapeutics, Vol. 82, No. 2-3, 1999, pp. 409-425. doi:10.1016/S0163-7258(98)00071-0
[90] D. Koul, R. Shen, Y. W. Kim, Y. Kondo, Y. Lu, J. Bankson, S. M. Ronen, D. L. Kirkpatrick, G. Powis and W. K. Yung, “Cellular and in Vivo Activity of a Novel PI3K Inhibitor, PX-866, against Human Glioblastoma,” Neuro-Oncology, Vol. 12, No. 6, 2010, pp. 559-569. doi:10.1093/neuonc/nop058
[91] G. Prasad, T. Sottero, X. Yang, S. Mueller, C. D. James, W. A. Weiss, M. Y. Polley, T. Ozawa, M. S. Berger, D. T. Aftab, M. D. Prados and D. A. Haas-Kogan, “Inhibition of PI3K/mTOR Pathways in Glioblastoma and Implications for Combination Therapy with Temozolomide,” Neuro-Oncology, Vol. 13, No. 4, 2011, pp. 384-392. doi:10.1093/neuonc/noq193
[92] N. Zhang, P. Wei, A. Gong, W. T. Chiu, H. T. Lee, H. Colman, H. Huang, J. Xue, M. Liu, Y. Wang, R. Sawaya, K. Xie, W. K. Yung, R. H. Medema, X. He and S. Huang, “FoxM1 Promotes Beta-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma Tumorigenesis,” Cancer Cell, Vol. 20, No. 4, 2011, pp. 427-442. doi:10.1016/j.ccr.2011.08.016
[93] T. Pulvirenti, M. Van Der Heijden, L. A. Droms, J. T. Huse, V. Tabar and A. Hall, “Dishevelled 2 Signaling promotes self-renewal and tumorigenicity in human gliomas,” Cancer Research, Vol. 71, No. 23, 2011, pp. 7280-7290. doi:10.1158/0008-5472.CAN-11-1531
[94] W. Roth, C. Wild-Bode, M. Platten, C. Grimmel, H. S. Melkonyan, J. Dichgans and M. Weller, “Secreted Frizzled-Related Proteins Inhibit Motility and Promote Growth of Human Malignant Glioma Cells,” Oncogene, Vol. 19, No. 37, 2000, pp. 4210-4220. doi:10.1038/sj.onc.1203783
[95] J. Satoh and Y. Kuroda, “Beta-Catenin Expression in Human Neural Cell Lines Following Exposure to Cytokines and Growth Factors,” Neuropathology, Vol. 20, No. 2, 2000, pp. 113-123. doi:10.1046/j.1440-1789.2000.00293.x
[96] C. Liu, Y. Tu, X. Sun, J. Jiang, X. Jin, X. Bo, Z. Li, A. Bian, X. Wang, D. Liu, Z. Wang and L. Ding, “Wnt/Beta-Catenin Pathway in Human Glioma: Expression Pattern and Clinical/Prognostic Correlations,” Clinical and Experimental Medicine, Vol. 11, No. 2, 2011, pp. 105-112. doi:10.1007/s10238-010-0110-9
[97] W. L. Lambiv, I. Vassallo, M. Delorenzi, T. Shay, A. C. Diserens, A. Misra, B. Feuerstein, A. Murat, E. Mig- liavacca, M. F. Hamou, D. Sciuscio, R. Burger, E. Do- many, R. Stupp and M. E. Hegi, “The Wnt Inhibitory Factor 1 (WIF1) is Targeted in Glioblastoma and Has a Tumor Suppressing Function Potentially by Induction of Senescence,” Neuro-Oncology, Vol. 13, No. 7, 2011, pp. 736-747. doi:10.1093/neuonc/nor036
[98] M. Kamino, M. Kishida, T. Kibe, K. Ikoma, M. Iijima, H. Hirano, M. Tokudome, L. Chen, C. Koriyama, K. Yamada, K. Arita and S. Kishida, “Wnt-5a Signaling is Correlated with Infiltrative Activity in Human Glioma by Inducing Cellular Migration and MMP-2,” Cancer Science, Vol. 102, No. 3, 2011, pp. 540-548. doi:10.1111/j.1349-7006.2010.01815.x
[99] G. Foltz, J. G. Yoon, H. Lee, L. Ma, Q. Tian, L. Hood and A. Madan, “Epigenetic Regulation of Wnt Pathway Antagonists in Human Glioblastoma Multiforme,” Genes Cancer, Vol. 1, No. 1, 2010, pp. 81-90. doi:10.1177/1947601909356103
[100] R. M. Zuniga, R. Torcuator, R. Jain, J. Anderson, T. Doyle, L. Schultz and T. Mikkelsen, “Rebound Tumour Progression after the Cessation of Bevacizumab Therapy in Patients with Recurrent High-Grade Glioma,” Journal of Neuro-Oncology, Vol. 99, No. 2, 2010, pp. 237-242. doi:10.1007/s11060-010-0121-0
[101] S. D. Rose and M. K. Aghi, “Mechanisms of Evasion to Antiangiogenic Therapy in Glioblastoma,” Clinical Neurosurgery, Vol. 57, No. 2010, pp. 123-128.
[102] M. Paez-Ribes, E. Allen, J. Hudock, T. Takeda, H. Okuyama, F. Vinals, M. Inoue, G. Bergers, D. Hanahan and O. Casanovas, “Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis,” Cancer Cell, Vol. 15, No. 3, 2009, pp. 220-231. doi:10.1016/j.ccr.2009.01.027
[103] A. Wick, N. Dorner, N. Schafer, S. Hofer, S. Heiland, D. Schemmer, M. Platten, M. Weller, M. Bendszus and W. Wick, “Bevacizumab Does Not Increase the Risk of Remote Relapse in Malignant Glioma,” Annals of Neurology, Vol. 69, No. 3, 2011, pp. 586-592. doi:10.1002/ana.22336
[104] E. C. Quant, A. D. Norden, J. Drappatz, A. Muzikansky, L. Doherty, D. Lafrankie, A. Ciampa, S. Kesari and P. Y. Wen, “Role of a Second Chemotherapy in Recurrent Malignant Glioma Patients who Progress on Bevacizumab,” Neuro-Oncology, Vol. 11, No. 5, 2009, pp. 550-555. doi:10.1215/15228517-2009-006
[105] O. Warburg, “On the Origin of Cancer Cells,” Science, Vol. 123, No. 3191, 1956, pp. 309-314. doi:10.1126/science.123.3191.309
[106] D. Hanahan and R. A. Weinberg, "Hallmarks of Cancer: the next generation." Cell. Vol.144, No. 5, 2011, pp. 646-674 doi:10.1016/j.cell.2011.02.013
[107] A. King and E. Gottlieb, “Glucose Metabolism and Programmed Cell Death: An Evolutionary and Mechanistic Perspective,” Current Opinion in Cell Biology, Vol. 21, No. 6, 2009, pp. 885-893. doi:10.1016/
[108] R. A. Cairns, I. S. Harris and T. W. Mak, “Regulation of Cancer Cell Metabolism,” Nature Reviews Cancer, Vol. 11, No. 2, 2011, pp. 85-95. doi:10.1038/nrc2981
[109] S. Gupta, A. Farooque, J. S. Adhikari, S. Singh and B. S. Dwarakanath, “Enhancement of Radiation and Chemotherapeutic Drug Responses by 2-Deoxy-D-Glucose in Animal Tumors,” Journal of Cancer Research and Therapeutics, Vol. 5, Suppl. 1, 2009, pp. S16-S20. doi:10.4103/0973-1482.55135
[110] J. M. Chang, J. W. Chung, H. J. Jae, H. Eh, K. R. Son, K. C. Lee and J. H. Park, “Local Toxicity of Hepatic Arterial Infusion of Hexokinase II Inhibitor, 3-Bromopyruvate: In Vivo Investigation in Normal Rabbit Model,” Academic Radiology, Vol. 14, No. 1, 2007, pp. 85-92. doi:10.1016/j.acra.2006.09.059
[111] D. Stieber, S. A. Abdul Rahim and S. P. Niclou, “Novel Ways to Target Brain Tumour Metabolism,” Expert Opinion on Therapeutic Targets, Vol. 15, No. 10, 2011, pp. 1227-1239. doi:10.1517/14728222.2011.588211
[112] Roche, “A Study of Avastin (Bevacizumab) in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma,” 2009-2012.

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