Therapeutic strategies for inhibiting invasion in glioblastoma

Expert Review of Neurotherapeutics

Volumn 9, Issue 4, 2009, Pages 519-534

  Drappatz, Jan ^a   Norden, Andrew D ^a   Wen, Patrick Y ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Angiogenesis; Anti tenascin antibody; C met inhibitor; Cilengitide; Extracellular matrix; Glioblastoma; Invasion; Migration; PI3K inhibitor; Scatter factor hepatocyte growth factor inhibitor; TGF

Indexed keywords

3 [1 (2,6 DICHLORO 3 FLUOROPHENYL)ETHOXY] 5 [1 (4 PIPERIDINYL) 1H PYRAZOL 4 YL] 2 PYRIDINYLAMINE; AMG 102; AP 12009; ARQ 197; AT 13387; AUY 922; BA 210; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; BEVACIZUMAB; BGT 226; BIIB 2001; BORTEZOMIB; CDX 110; CEDIRANIB; CETUXIMAB; CILENGITIDE; CURCUMIN; DASATINIB; DEFOROLIMUS; DISULFIRAM; ERLOTINIB; EVEROLIMUS; FASUDIL; FINGOLIMOD; GC 1008; GEFITINIB; GSK 1363089; GSK 690693; HYDROXYUREA; IMATINIB; INCB 3619; INCYCLINIDE; JNJ 38877605; LAPATINIB; LITHIUM; MARIMASTAT; MGCD 265; MK 0646; MK 220; MP 470; NEURADIAB; NIMOTUZUMAB; PF 00562271; PF 03446962; PF 0421790; PF 04554878; PLERIXAFOR; PRINOMASTAT; PX 866; RAPAMYCIN; REBIMASTAT; SALAZOSULFAPYRIDINE; SF 226; STA 9090; TANESPIMYCIN HYDROQUINONE; TANOMASTAT; TEMOZOLOMIDE; TEMSIROLIMUS; TP 38; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; XL 147; XL 184; XL 765;

ALLOPATHY; ANGIOGENESIS; ANTIANGIOGENIC THERAPY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTHRALGIA; BLOOD BRAIN BARRIER; CANCER INHIBITION; CANCER INVASION; CANCER SURVIVAL; CELL ADHESION; CELL INTERACTION; CELL MIGRATION; CHEMOTHERAPY; CLINICAL TRIAL; CYTOSKELETON; DISEASE FREE SURVIVAL; DISSOCIATION; DRUG EFFICACY; DRUG INHIBITION; DRUG MECHANISM; DRUG MEGADOSE; DRUG TARGETING; EXTRACELLULAR MATRIX; GENE REARRANGEMENT; GLIOBLASTOMA; GLIOMA CELL; HUMAN; INTRACELLULAR MEMBRANE; MOLECULAR INTERACTION; NEURAL STEM CELL; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; TENDON PAIN; TREATMENT DURATION; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT;

BRAIN NEOPLASMS; GLIOBLASTOMA; HUMANS; MAGNETIC RESONANCE IMAGING; MODELS, BIOLOGICAL; NEOPLASM INVASIVENESS;

EID: 66349107700     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.10     Document Type: Review

References (178)

1. Wen PY, Kesari S. Malignant gliomas in adults. N Engl.J. Med.359, 492-507 (2008).
2. Furnari FB, Fenton T, Bachoo RM et al.Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev.21, 2683-2710 (2007).
3. Giese A, Bjerkvig R, Berens M et al.Cost of migration: invasion of malignant gliomas and implications for treatment. J. Clin. Oncol.21, 1624-1636 (2003).
4. Giese A, Westphal M. Glioma invasion in the central nervous system. Neurosurgery39, 235-252 (1996).
5. WHO Classification Of Tumours Of The Central Nervous System (4th Edition).Louis DN, Ohgaki H, Wiestler OD et al.(Eds). IARC, Lyon, France (2007).
6. Bernsen H, Van der LaakJ, Kusters B et al.Gliomatosis cerebri: quantitative proof of vessel recruitment by cooptation instead of angiogenesis./. Neurosurg.103, 702-706 (2005).
7. Fischer I, Gagner JP, Law M et al.Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol.15, 297-310 (2005).
8. Ganslandt O, Stadlbauer A, Fahlbusch R et al.Proton magnetic resonance spectroscopic imaging integrated into image-guided surgery: correlation to standard magnetic resonance imaging and tumor cell density. Neurosurgery56, 291-298 (2005).
9. Vredenburgh J, Desjardins A, Herndon JN et al.Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res.13, 253-1259 (2007).
10. Cloughesy T, Prados M, Wen P 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) /. Clin. Oncol.26 (2008) (Abstract 2010b).
11. Norden AD, Drappatz J, Wen PY. Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol.7, 1152-1160 (2008).
12. Norden AD, Young GS, Setayesh K et al.Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology70, 779-787 (2008).
13. Narayana A, Raza S, Golfinos JG et al.Bevacizumab therapy in recurrent high grade glioma: impact on local control and survival. J. Clin. Oncol.26(SuppL), (2008) (Abstract 13000).
14. Lamszus K, Kunkel P, Westphal M. Invasion as limitation to anti-angiogenic glioma therapy. Acta Neurochir. Suppl.88, 169-177 (2003).
15. Kunkel P, Ulbricht U, Bohlen P et al.Inhibition of glioma angiogenesis and growth in vivoby systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res.61, 6624-6628 (2001).
16. Rubenstein J, Kim J, Ozawa T et al.Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia2, 306-314 (2000).
17. Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev. Anticancer Ther.7, 1537-1560 (2007).
18. Fischer I, Cunliffe CH, Bollo RJ et al.High-grade glioma before and after treatment with radiation and Avastin: initial observations. Neuro Oncol.10, 700-708 (2008).
19. Rao J. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat. Rev. Cancer3, 489-501 (2003).
20. Bellail AC, Hunter SB, Brat DJ et al.Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int. J. Biochem. Cell Biol.36, 1046-1069 (2004).
21. Bello L, Giussani C, Carrabba G et al.Angiogenesis and invasion in gliomas. Cancer Treat. Res.117, 263-284 (2004).
22. Gunther W, Skaftnesmo KO, Arnold H et al.Molecular approaches to brain tumour invasion. Acta Neurochir. (Wien)145, 1029-1036 (2003).
23. Nakada M, Nakada S, Demuth T et al.Molecular targets of glioma invasion. Cell. Mol. LifeSci.64, 458-478 (2007).
24. Salhia B, Tran NL, Symons M et al.Molecular pathways triggering glioma cell invasion. Expert Rev. Mol. Diagn.6, 613-626 (2006).
25. Suzuki SO, Iwaki T. Dynamic analysis of glioma cells: looking into "movement phenotypes". Neuropathology25, 254-262 (2005).
26. Tonn JC, Goldbrunner R. Mechanisms of glioma cell invasion. Acta Neurochir. Suppl.88, 163-167 (2003).
27. Claes A, Idema AJ, Wesseling P. Diffuse glioma growth: a guerilla war. Acta Neuropathol.114,443-458 (2007).
28. Hoelzinger DB, Demuth T, Berens ME. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. /. Natl Cancer Inst.99, 1583-1593 (2007).
29. Singh S, Dirks PB. Brain tumor stem cells: identification and concepts. Neurosurg. Clin. N Am.18, 31-38, viii (2007).
30. Stiles CD, Rowitch DH. Glioma stem cells: a midterm exam. Neuron58, 832-846 (2008).
31. Dirks PB. Cancer: stem cells and brain tumours. Nature444, 687-688 (2006).
32. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas.N. Engl.J. Med.353, 811-822 (2005).
33. Singh SK, Hawkins C, Clarke ID et al.Identification of human brain tumour initiating cells. Nature432, 396-401 (2004).
34. Liu G, Yuan X, Zeng Z et al.Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer5, 67 (2006).
35. Zeppernick F, Ahmadi R, Campos B et al.Stem cell marker CD133 affects clinical outcome in glioma patients. Clin. Cancer Res.14, 123-129 (2008).
36. Joo KM, Kim SY, Jin X et al.Clinical and biological implications of CD133- positive and CD133-negative cells in glioblastomas. Lab. Invest.88, 808-815 (2008).
37. Wang J, Sakariassen PO, Tsinkalovsky O et al.CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int. J. Cancer122, 761-768 (2008).
38. Widera D, Kaus A, Kaltschmidt C et al.Neural stem cells, inflammation and NF-KB: basic principle of maintenance and repair or origin of brain tumours?/. Cell. Mol. Med.12, 459-470 (2008).
39. Widera D, Mikenberg I, Kaltschmidt B et al.Potential role of NF-KB in adult neural stem cells: the underrated steersman? Int. J. Dev. Neurosci.24, 91-102 (2006).
40. Murai T, Miyazaki Y, Nishinakamura H et al.Engagement of CD44 promotes Rac activation and CD44 cleavage during tumor cell migration. /. Biol. Chem.279, 4541-4550 (2004).
41. Asano K, Duntsch CD, Zhou Q et al.Correlation of N-cadherin expression in high grade gliomas with tissue invasion. J. Neurooncol.70, 3-15 (2004).
42. Todaro L, Christiansen S, Varela M et al.Alteration of serum and tumoral neural cell adhesion molecule (NCAM) isoforms in patients with brain tumors. J. Neurooncol.83, 135-144 (2007).
43. Zamecnik J. The extracellular space and matrix of gliomas. Acta Neuropathol.110, 435-442 (2005).
44. Gladson CL, Cheresh DA. Glioblastoma expression of vitronectin and the avP3 integrin. Adhesion mechanism for transformed glial cells./. Clin. Invest.88, 1924-1932 (1991).
45. Sarkar S, Nuttall RK, Liu S et al.Tenascin-C stimulates glioma cell invasion through matrix metalloproteinase-12. Cancer Res. 66,11771-11780 (2006).
46. Brack SS, Silacci M, Birchler M et al.Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C. Clin. Cancer Res.12, 3200-3208 (2006).
47. Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett.244, 143-163 (2006).
48. Kunigal S, Gondi CS, Gujrati M et al.SPARC-induced migration of glioblastoma cell lines via uPA-uPAR signaling and activation of small GTPase RhoA. Int. J. Oncol.29, 1349-1357 (2006).
49. Tucker GC. Integrins: molecular targets in cancer therapy. Curr. Oncol. Rep.8, 96-103 (2006).
50. Ridley AJ, Schwartz MA, Burridge K et al.Cell migration: integrating signals from front to back. Science302, 1704-1709 (2003).
51. Wang M, Wang T, Liu S et al.The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol.20, 65-72 (2003).
52. Koutroulis I, Zarros A, Theocharis S. The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies: a chance for the development of targeted therapeutic approaches? Expert Opin. Ther. Targets12, 1577-1586 (2008).
53. Kodama T, Ikeda E, Okada A et al.ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am. J. Pathol.165, 1743-1753 (2004).
54. Lakka SS, Gondi CS, Yanamandra N et al.Inhibition of cathepsin B and MMP-9gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. Oncogene23, 4681-4689 (2004).
55. Gondi CS, Lakka SS, Dinh DH et al.Downregulation of uPA, uPAR and MMP-9 using small, interfering, hairpin RNA (siRNA) inhibits glioma cell invasion, angiogenesis and tumor growth. Neuron Glia Biol.1, 165-176 (2004).
56. Wang L, Zhang ZG, Zhang RL et al.Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration./. Neurosci.26, 5996-6003 (2006).
57. Golembieski WA, Thomas SL, Schultz CR et al.HSP27 mediates SPARC-induced changes in glioma morphology, migration, and invasion. Glia56, 1061-1075 (2008).
58. Stylli SS, Kaye AH, Lock P. Invadopodia: at the cutting edge of tumour invasion. J. Clin. Neurosci.15, 725-737 (2008).
59. Chan AY, Coniglio SJ, Chuang YY et al.Roles of the Racl and Rac3 GTPases in human tumor cell invasion. Oncogene24, 7821-7829 (2005).
60. Luwor RB, Kaye AH, Zhu HJ. Transforming growth factor-P (TGF-P) and brain tumours. J. Clin. Neurosci.15, 845-855 (2008).
61. Abounader R, Laterra J. Scatter factor/ hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol.7, 436-451 (2005).
62. Grotegut S, von Schweinitz D, Christofori G et al.Hepatocyte growth factor induces cell scattering through MAPK/Egr-1- mediated upregulation of Snail. EMBOJ.25, 3534-3545 (2006).
63. Eckerich C, Zapf S, Fillbrandt R et al.Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration. Int. J. Cancer121, 276-283 (2007).
64. Wang H, Shen W, Huang H et al.Insulin-like growth factor binding protein 2 enhances glioblastoma invasion by activating invasion-enhancing genes. Cancer Res.63, 4315-4321 (2003).
65. Song SW, Fuller GN, Khan A et al.IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proc. NatlAcad. Sci. USA100, 13970-13975 (2003).
66. Bruna A, Darken RS, Rojo F et al.High TGFP-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-Bgene. Cancer Cell11, 147-160 (2007).
67. Nakada M, Drake KL, Nakada S et al.Ephrin-B3 ligand promotes glioma invasion through activation of Racl. Cancer Res. 66,8492-8500 (2006).
68. Nakada M, NiskaJA, Tran NL et al.EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. Am.]. Pathol. 167,565-576 (2005).
69. Wang LF, Fokas E, Juricko J et al.Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. BMC Cancer8, 79 (2008).
70. Yepes M. TWEAK and the central nervous system. Mol. Neurobiol.35, 255-265 (2007).
71. Tran NL, McDonough WS, Savitch BA et al.The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fnl4) signaling system regulates glioma cell survival via NFKB pathway activation and BCL-XL/BCL-Wexpression./. Biol. Chem.280, 3483-3492 (2005).
72. Tran NL, McDonough WS, Donohue PJ et al.The human Fnl4 receptor gene is up-regulated in migrating glioma cells in vitroand overexpressed in advanced glial tumors. Am. J. Pathol.162, 1313-1321 (2003).
73. Ehtesham M, Winston JA, Kabos P et al.CXCR4 expression mediates glioma cell invasiveness. Oncogene25, 2801-2806 (2006).
74. Wu M, Chen Q, Li D et al.LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 a/CXCR4-mediated ERK1/2 and Akt signaling pathways. J. Cell. Biochem.103, 245-255 (2008).
75. Guo P, Imanishi Y, Cackowski FC et al.Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 y2correlates with the invasiveness of human glioma. Am. J. Pathol.166, 877-890 (2005).
76. Voelzke WR, Petty WJ, Lesser GJ. Targeting the epidermal growth factor receptor in high-grade astrocytomas. Curr. Treat. Options Oncol.9, 23-31 (2008).
77. Anliker B, Chun J. Cell surface receptors in lysophospholipid signaling. Semin. Cell. Dev. Biol.15, 457-465 (2004).
78. Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat. Rev. Mol. Cell. Biol.6, 56-68 (2005).
79. Lipinski CA, Tran NL, Menashi E et al.The tyrosine kinase pyk2 promotes migration and invasion of glioma cells. Neoplasial,435-445 (2005).
80. Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J. Clin. Oncol.23, 2411-2422 (2005).
81. Nomura N, Nomura M, Mizuki N et al.Racl mediates phorbol 12-myristate 13-acetate-induced migration of glioblastoma cells via paxillin. Oncol. Rep.20,705-711 (2008).
82. Webb DJ, Donais K, Whitmore LA et al.FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol.6, 154-161 (2004).
83. Lund CV, Nguyen MT, Owens GC et al.Reduced glioma infiltration in Src-deficient mice./. Neurooncol.78, 19-29 (2006).
84. Angers-Loustau A, Hering R, Werbowetski TE et al.SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions. Mol. Cancer Res.2, 595-605 (2004).
85. Tamura M, Gu J, Matsumoto K et al.Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280,1614-1617 (1998).
86. Furukawa K, Kumon Y, Harada H et al. PTENgene transfer suppresses theinvasive potential of human malignant gliomas by regulating cell invasion-related molecules. Int. J. Oncol.29, 73-81 (2006).
87. Guha A, Mukherjee J. Advances in the biology of astrocytomas. Curr. Opin. Neurol.17, 655-662 (2004).
88. Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene27, 5416-5430 (2008).
89. Joy AM, Beaudry CE, Tran NL et al.Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. J. Cell Sci.116, 4409-4417 (2003).
90. Zhang Y, Zhang N, Dai B et al.FoxMlB transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. Cancer Res.68, 8733-8742 (2008).
91. Aggarwal BB. Nuclear factor-KB: the enemy within. Cancer Cell 6,203-208 (2004).
92. Van Waes C. Nuclear factor-KB in development, prevention, and therapy of cancer. Clin. Cancer Res.13, 1076-1082 (2007).
93. Nagai S, Washiyama K, Kurimoto M et al.Aberrant nuclear factor-KB activity and its participation in the growth of human malignant astrocytoma./. Neurosurg.96, 909-917 (2002).
94. TsunodaK, Kitange G, AndaT et al.Expression of the constitutively activated RelA/NF-KB in human astrocytic tumors and the in vitroimplication in the regulation of urokinase-type plasminogen activator, migration, and invasion. Brain Tumor Pathol.22, 79-87 (2005).
95. Smith D, Shimamura T, Barbera S et al.NF-KB controls growth of glioblastomas/ astrocytomas. Mol. Cell. Biochem.307, 141-147 (2008).
96. Karin M. Nuclear factor-KB in cancer development and progression. Nature441, 431-436 (2006).
97. Ahn KS, Sethi G, Aggarwal BB. Nuclear factor-KB: from clone to clinic. Curr. Mol. Med.7, 619-637 (2007).
98. Lee CH, Jeon YT, Kim SH et al.NF-KB as a potential molecular target for cancer therapy. Biofactors29, 19-35 (2007).
99. Weaver KD, Yeyeodu S, Cusack JC Jr et al.Potentiation of chemotherapeutic agents following antagonism of nuclear factor KB in human gliomas. J. Neurooncol.61, 187-196 (2003).
100. Chuang YY, Tran NL, Rusk N et al.Role of synaptojanin 2 in glioma cell migration and invasion. Cancer Res.64, 8271-8275 (2004).
101. SalhiaB, Tran NL, Chan Ket al.The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma.Am. J. Pathol.173, 1828-1838 (2008).
102. Dey N, Crosswell HE, De P et al.The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res.68, 1862-1871 (2008).
103. Stupp R, Mason WP, van den Bent MJ et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl.J. Med.352, 987-996 (2005).
104. Wick W, Wick A, Schulz JB et al.Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res.62, 1915-1919 (2002).
105. Schiff D, Purow B. Bevacizumab in combination with irinotecan for patients with recurrent glioblastoma multiforme. Nat. Clin. Pract. Oncol.5, 186-187 (2008).
106. Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al.Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol.25, 4722-4729 (2007).
107. Tonn J, Kerkau S, Hanke A et al.Effect of synthetic matrix-metalloproteinase inhibitors on invasive capacity and proliferation of human malignant gliomas in vitro. Int. J. Cancer80, 764-772 (1999).
108. Levin VA, Phuphanich S, Yung WK et al.Randomized, double-blind, placebo- controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation./. Neurooncol.78, 295-302 (2006).
109. Levin V, Phuphanich S, Yung W et al.Randomized, double-blind, placebo- controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation. J. Neurooncol.78, 295-302 (2006).
110. Groves MD, Puduvalli VK, Hess KR et al.Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J. Clin. Oncol.20, 1383-1388 (2002).
111. 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.17, 2572-2578 (1999).
112. Groves MD, Puduvalli VK, Conrad CA et al.Phase II trial of temozolomide plus marimastat for recurrent anaplastic gliomas: a relationship among efficacy, joint toxicity and anticonvulsant status. J. Neurooncol.80, 83-90 (2006).
113. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science295, 2387-2392 (2002).
114. Blazquez C, Salazar M, Carracedo A et al.Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res.68, 1945-1952 (2008).
115. Gabriely G, Wurdinger T, Kesari S et al.MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol. Cell. Biol.28, 5369-5380 (2008).
116. Reardon DA, Nabors LB, Stupp R et al.Cilengitide: an integrin-targeting arginine- glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin. Investig. Drugs17, 1225-1235 (2008).
117. Yamada S, Bu XY, Khankaldyyan V et al.Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery59, 1304-1312 (2006).
118. Nabors LB, Mikkelsen T, Rosenfeld SS et al.Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma./. Clin. Oncol.25, 1651-1657 (2007).
119. 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.26, 5610-5617 (2008).
120. Stupp R, Goldbrunner R, Neyns B et al.Mature results of a Phase I/IIa trial of the integrin inhibitor cilengitide (EMD121974) added to standard concomitant and adjuvant temozolomide and radiotherapy for newly diagnosed glioblastoma. Neuro Oncol.9, 517 (2007).
121. Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin. Investig. Drugs17, 1717-1734 (2008).
122. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer A,335-348 (2004).
123. Chang SM, Wen P, Cloughesy T et al.Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest. New Drugs23, 357-361 (2005).
124. Galanis E, Buckner J, Maurer M et al.Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol.23, 5294-5304 (2005).
125. Cloughesy TF, Yoshimoto K, Nghiemphu P et al.Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med.5(1), e8 (2008).
126. an QW, Knight ZA, Goldenberg DD et al.A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell%341-349 (2006).
127. Maira SM, Stauffer F, Brueggen J et al.Identification and characterization of N VP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivoantitumor activity. Mol. Cancer Ther.7, 1851-1863 (2008).
128. Momota H, Nerio E, Holland EC. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res.65, 7429-7435 (2005).
129. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene27, 5511-5526 (2008).
130. Ravi R, Bedi A. NF-KB in cancer - a friend turned foe. Drug Resist. Updat.7, 53-67 (2004).
131. Yin D, Zhou H, Kumagai T et al.Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene24, 344-354 (2005).
132. La Ferla-Bruhl K, Westhoff MA, Karl S et al.NF-KB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition. Oncogene 26,571-582 (2007).
133. Robe PA, Martin D, Albert A et al.A Phase 1-2, prospective, double blind, randomized study of the safety and efficacy of sulfasalazine for the treatment of progressing malignant gliomas: study protocol of [ISRCTN45828668]. BMC Cancer6, 29 (2006).
134. Ning S, Knox SJ. Increased cure rate of glioblastoma using concurrent therapy with radiotherapy and arsenic trioxide. Int. J. Radiat. Oncol. Biol. Phys.60, 197-203 (2004).
135. Aoki H, Takada Y, Kondo S et al.Evidence that curcumin suppresses the growth of malignant gliomas in vitroand in vivothrough induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol. Pharmacol.72, 29-39 (2007).
136. Lovborg H, Oberg F, Rickardson L et al.Inhibition of proteasome activity, nuclear factor-KB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer118, 1577-1580 (2006).
137. Martin V, Herrera F, Garcia-Santos G et al.Signaling pathways involved in antioxidant control of glioma cell proliferation. Free Radic. Biol. Med.42, 1715-1722 (2007).
138. Laguillier C, Hbibi AT, Baran-Marszak F et al.Cell death in NF-KB-dependent tumour cell lines as a result of NF-KB trapping by linker-modified hairpin decoy oligonucleotide. FEES Lett.581, 1143-1150 (2007).
139. Olivier S, Robe P, Bours V. Can NF-KB be a target for novel and efficient anti-cancer agents? Biochem. Pharmacol.72, 1054-1068 (2006).
140. Roccaro AM, Hideshima T, Richardson PG et al.Bortezomib as an antitumor agent. Curr. Pharm. Biotechnol.7, 441-448 (2006).
141. Takada Y, Bhardwaj A, Potdar P et al.Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-KB activation, inhibition of expression of cyclooxygenase-2 and cyclin Dl, and abrogation of tumor cell proliferation. Oncogene23, 9247-9258 (2004).
142. Robe PA, Bentires-Alj M, Bonif M et al. In vitroand in vivoactivity of the nuclear factor-KB inhibitor sulfasalazine in human glioblastomas. Clin. Cancer Res.10, 5595-5603 (2004).
143. Kapahi P, Takahashi T, Natoli G < Inhibition of NF-KB activation by arsenite through reaction with a critical cysteine in the activation loop of IKB kinase. J. Biol. Chem.275, 36062-36066 (2000).
144. Panchal HD, Vranizan K, Lee CY et al.Early anti-oxidative and anti-proliferative curcumin effects on neuroglioma cells suggest therapeutic targets. Neurochem. Res.33, 1701-1710 (2008).
145. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFKB transcription factors. J. Neurochem.102, 522-538 (2007).
146. Hatcher H, Planalp R, Cho J et al.Curcumin: from ancient medicine to current clinical trials. Cell. Mol. Life Sci.65, 1631-1652 (2008).
147. Isomura I, Morita A. Regulation of NF-KB signaling by decoy oligodeoxynucleotides. Microbiol. Immunol.50, 559-563 (2006).
148. Nowicki MO, Dmitrieva N, Stein AM et al.Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neuro Oncol.10(5), 690-699 (2008).
149. Kotliarova S, Pastorino S, Kovell LC et al.Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-KB, and glucose regulation. Cancer Res.68, 6643-6651 (2008).
150. Hjelmeland MD, Hjelmeland AB, Sathornsumetee S et al.SB-431542, a small molecule transforming growth factor-P-receptor antagonist, inhibits human glioma cell line proliferation and motility. Mol. Cancer Ther.3, 737-745 (2004).
151. Uhl M, Aulwurm S, Wischhusen J et al.SD-208, a novel transforming growth factor-P receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitroand in vivo. Cancer Res.64, 7954-7961 (2004).
152. Hau P, Jachimczak P, Schlingensiepen R et al.Inhibition of TGF-P2 with AP 12009 in recurrent malignant gliomas: from preclinical to Phase I/II studies. Oligonucleotid.es Y7,201-212 (2007).
153. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A et al.Targeted tumor therapy with the TGF-P2 antisense compound AP 12009. Cytokine Growth Factor Rev.17, 129-139 (2006).
154. Shi Q, Hjelmeland AB, Keir ST et al. A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol. Carcinog.46, 488-496 (2007).
155. Reardon DA, Zalutsky MR, Akabani G et al.A pilot study: 1311-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost. Neuro Oncol.10, 182-189 (2008).
156. Reardon D, Akabani G, Coleman R et al.Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: Phase II study results. J. Clin. Oncol.24, 115-122 (2006).
157. Brockmann MA, Papadimitriou A, Brandt M et al.Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte growth factor-antagonist NK4. Clin. Cancer Res.9, 4578-4585 (2003).
158. Martens T, Schmidt NO, Eckerich C et al.A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin. Cancer Res.12, 6144-6152 (2006).
159. Reardon D, Cloughsey TF, Raizer JJ et al.Phase II study of AMG 102, a fully human neutralizing antibody against hepatocyte growth factor/scatter factor, in patients with recurrent glioblastoma multiforme. J. Clin. Oncol. Suppl.26, (2008) (Abstract 2051).
160. Burgess T, Coxon A, Meyer S et al.Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res. 66,1721-1729 (2006).
161. Nicholas MK, Lukas RV, Jafri NF et al.Epidermal growth factor receptor - mediated signal transduction in the development and therapy of gliomas. Clin. Cancer Res.12, 7261-7270 (2006).
162. Brandes AA, Franceschi E, Tosoni A et al.Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin. Cancer Res.14, 957-960 (2008).
163. Mellinghoff IK, Wang MY, Vivanco I et al.Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl. J. Med.353, 2012-2024 (2005).
164. Martens T, Laabs Y, Gunther HS et al.Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. Clin. Cancer Res.14, 5447-5458 (2008).
165. Lamszus K, Brockmann MA, Eckerich C et al.Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin. Clin. Cancer Res.11, 4934-4940 (2005).
166. Sathornsumetee S, DesjardinsA, Vredenburgh J et al.Safety and efficacy of bevacizumab and erlotinib for recurrent glioblastoma patients in a Phase II study. Neuro Oncol.10, 827 (MA-840) (2008).
167. Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett. Til,139-147 (2006).
168. Lamszus K, Heese O, Westphal M. Angiogenesis-related growth factors in brain tumors. Cancer Treat. Res.117, 169-190 (2004).
169. Cattaneo MG, Gentilini D, Vicentini LM. Deregulated human glioma cell motility: inhibitory effect of somatostatin. Mol. Cell. Endocrinol.256, 34-39 (2006).
170. Natarajan M, Stewart JE, Golemis EA et al.HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene25, 1721-1732 (2006).
171. 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.23, 9359-9368 (2005).
172. 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.12, 4899-4907 (2006).
173. 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.26, 4659-4665 (2008).
174. Lassman A, Wang W, Gilbert M et al.Phase II trial of dasatinib for recurrent glioblastoma. Neuro Oncol.10, 824 (MA-830) (2008).
175. Sauvageot CM, Weatherbee JL, Kesari S et al.Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol.DOI: 15228517-2008-060vl (2008) (Epub ahead of print).
176. Workman P, Burrows F, Neckers L et al.Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann. NYAcad. Sci.1113, 202-216 (2007).
177. Kim MS, Kwak HJ, Lee JW et al.17-Allylamino-17- demethoxygeldanamycin down-regulates hyaluronic acid-induced glioma invasion by blocking matrix metalloproteinase-9 secretion. Mol. Cancer Res.6, 1657-1665 (2008).
178. Corsten MF, Shah K. Therapeutic stem-cells for cancer treatment: hopes and hurdles in tactical warfare. Lancet Oncol.9, 376-384 (2008).