A novel treatment for glioblastoma: Integrin inhibition

Expert Review of Neurotherapeutics

Volumn 12, Issue 4, 2012, Pages 421-435

  Chamberlain, Marc C ^a   Cloughsey, Timothy ^b   Reardon, David A ^c   Wen, Patrick Y ^d  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c DUKE UNIVERSITY   (United States)

^d HARVARD MEDICAL SCHOOL   (United States)

Author keywords

angiogenic inhibition; antiproliferative; cilengitide; glioblastoma; integrins

Indexed keywords

264 RAD; ANGIOGENESIS INHIBITOR; ANTICOAGULANT AGENT; ANTICONVULSIVE AGENT; ANTINEOPLASTIC AGENT; BEVACIZUMAB; CEDIRANIB; CELASTROL; CETUXIMAB; CILENGITIDE; CORTICOSTEROID; DI 17E6; E 7820; ETARACIZUMAB; GLPG 0187; HYD 1; IMGN 388; INTEGRIN; INTEGRIN INHIBITOR; INTETUMUMAB; IRINOTECAN; MK 0429; MONOCLONAL ANTIBODY; N ACETYLPROLYLHISTIDYLSERYLCYSTEINYLASPARAGINE AMIDE; NATALIZUMAB; PEPTIDOMIMETIC AGENT; PF 04605412; TEMOZOLOMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VOLOCIXIMAB;

ANGIOGENESIS; ANTICOAGULANT THERAPY; BLEEDING; BONE CANCER; BONE METASTASIS; CANCER CHEMOTHERAPY; CANCER INCIDENCE; CANCER INVASION; CANCER RADIOTHERAPY; CANCER RECURRENCE; CANCER SURVIVAL; CASTRATION RESISTANT PROSTATE CANCER; CELL MOTILITY; CELL PROLIFERATION; COLORECTAL CANCER; CYTOSKELETON; DRUG DOSE ESCALATION; DRUG TARGETING; EDEMA; GENE MUTATION; GENETIC ANALYSIS; GLIOBLASTOMA; HEAD AND NECK CANCER; HUMAN; HYPERGLYCEMIA; HYPONATREMIA; KIDNEY CARCINOMA; LUNG NON SMALL CELL CANCER; LYMPHOMA; MELANOMA; MOLECULAR BIOLOGY; MULTIPLE MYELOMA; MULTIPLE SCLEROSIS; NEOPLASM; NONHUMAN; PANCREAS CANCER; PERITUMORAL EDEMA; PHENOTYPE; PROSTATE CANCER; PROTEIN EXPRESSION; REVIEW; SEIZURE; SIGNAL TRANSDUCTION; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; TREATMENT RESPONSE; VENOUS THROMBOEMBOLISM;

ANIMALS; ANTINEOPLASTIC AGENTS; BRAIN NEOPLASMS; GLIOBLASTOMA; HUMANS; INTEGRINS;

EID: 84860289825     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.11.188     Document Type: Review

References (100)

1. Wen PY, Kesari S. Malignant gliomas in adults. N. Engl. J. Med. 359(5), 492-507 (2008). The best and most recent overview of gliomas and treatment.
2. Grossman SA, Ye X, Piantadosi S et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin. Cancer Res. 16(8), 2443-2449 (2010). Standard of care - that is, temozolomide followed by bevicizumab - results in an improvement of overall survival in patients with newly diagnosed glioblastoma (GBM).
3. Moustakas A, Kreisl TN. New treatment options in the management of glioblastoma multiforme: A focus on bevacizumab. Oncol. Targets Ther. 3, 27-38 (2010).
4. Parsons DW, Jones S, Zhang X et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897), 1807-1812 (2008).
5. Lee SM, Koh HJ, Park DC, Song BJ, Huh TL, Park JW. Cytosolic NADP(+)- dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol. Med. 32(11), 1185-1196 (2002). (Pubitemid 34603355)
6. Kim SY, Lee SM, Tak JK, Choi KS, Kwon TK, Park JW. Regulation of singlet oxygen-induced apoptosis by cytosolic NADP(+)-dependent isocitrate dehydrogenase. Mol. Cell Biochem. 302(1-2), 27-34 (2007). (Pubitemid 47202317)
7. Reardon DA, Rich JN, Friedman HS, Bigner DD. Recent advances in the treatment of malignant astrocytoma. J. Clin. Oncol. 24(8), 1253-1265 (2006). (Pubitemid 46622028)
8. Bredel M, Scholtens DM, Yadav AK et al. NFKBIA deletion in glioblastomas. N. Engl. J. Med. 364(7), 627-637 (2011).
9. Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987-996 (2005). The original study demonstrating the value of adjuvant temozolomide in newly diagnosed GBM. (Pubitemid 40349501)
10. Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase 3 study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10(5), 459-466 (2009).
11. Yung WK, Prados MD, Yaya-Tur R et al. Multicenter Phase 2 trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse: Temodal brain tumor group. J. Clin. Oncol. 17(9), 2762-2771 (1999). (Pubitemid 29415233)
12. Wong ET, Hess KR, Gleason MJ et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto Phase 2 clinical trials. J. Clin. Oncol. 17(8), 2572-2578 (1999). (Pubitemid 29368260)
13. Yung WK, Albright RE, Olson J et al. A Phase 2 study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br. J. Cancer 83(5), 588-593 (2000). (Pubitemid 30636298)
14. Perry JR, Bélanger K, Mason WP et al. Phase 2 trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J. Clin. Oncol. 28(12), 2051-2057 (2010).
15. Wick A, Pascher C, Wick W et al. Rechallenge with temozolomide in patients with recurrent gliomas. J. Neurol. 256(5), 734-741 (2009).
16. Friedman HS, Prados MD, Wen PY et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27(28), 4733-4740 (2009). One of two trials to demonstrate the value of bevacizumab in the treatment of recurrent GBM that resulted in approval for this indication.
17. Kreisl TN, Kim L, Moore K et al. Phase 2 trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27(5), 740-745 (2009). One of two trials to demonstrate the value of bevacizumab in the treatment of recurrent GBM that resulted in approval for this indication.
18. Folkman J. Angiogenesis: An organizing principle for drug discovery? Nat. Rev. Drug Discov. 6(4), 273-286 (2007). (Pubitemid 46505878)
19. Dunn IF, Heese O, Black PM. Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J. Neuro. Oncol. 50(1-2), 121-137 (2000). (Pubitemid 32169649)
20. Keunen O, Johansson M, Oudin A et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc. Natl Acad. Sci. 108(9), 3749-3754 (2011).
21. Norden AD, Young GS, Setayesh K et al. Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence. Neurology 70(10), 779-787 (2008).
22. Narayana A, Kunnakkat SD, Medabalmi P et al. Change in pattern of relapse after antiangiogenic therapy in high-grade glioma. Int. J. Radiat. Oncol. Biol. Phys. 82(1), 77-82 (2012).
23. Chamberlain MC. Radiographic patterns of relapse in glioblastoma. J. Neuro. Oncol. 101(2), 319-323 (2011).
24. Pope WB, Xia Q, Paton VE et al. Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab. Neurology 76(5), 432-437 (2011).
25. Wick A, Dörner N, Schäfer N et al. Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann. Neurol. 69(3), 586-592 (2011).
26. Hanahan D, Weinberg R. The hallmarks of cancer. Cell 100(1), 57-70 (2000). (Pubitemid 30046295)
27. Heddleston JM, Li Z, Hjelmeland AB, Rich AB. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8(20), 3274-3284 (2009).
28. Zhihong L, Wang H, Eyler CE, Hjelmeland AB, Rich JN. Turning cancer stem cells inside out: An exploration of glioma stem cell signaling pathways. J. Biol. Chem. 284(25), 16705-16709 (2009).
29. Stupp R, Ruegg C. Integrin inhibitors reaching the clinic. J. Clin. Oncol. 25(13), 1637-1638 (2007). (Pubitemid 46797938)
30. 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(10), 2411-2422 (2005). (Pubitemid 46218735)
31. Folkman J. What is the evidence that tumors are angiogenesis dependent? J. Natl Cancer Inst. 82(1), 4-6 (1990). (Pubitemid 20020880)
32. Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: Therapeutic implications. Semin. Oncol. 29(6 Suppl. 16), 10-14 (2002).
33. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3), 353-364 (1996). (Pubitemid 26272076)
34. Folkman J. Is angiogenesis an organizing principle in biology and medicine? J. Pediatr. Surg. 42(1), 1-11 (2007). (Pubitemid 46043358)
35. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120(3), 694-705 (2010).
36. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29(6 Suppl. 16), 15-18 (2002).
37. 5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol. 7(3), 339-354 (2011).
38. Ruoslahti E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12, 697-715 (1996). (Pubitemid 26422728)
39. Hynes RO. Integrins: Bidirectional, allosteric signaling machines. Cell 110(6), 673-687 (2002). (Pubitemid 35283958)
40. Legate KR, Wickstrom SA, Fassler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 23(4), 397-418 (2009).
41. Contois L, Akalu A, Brooks PC. Integrins as 'functional hubs' in the regulation of pathological angiogenesis. Semin. Cancer Biol. 19(5), 318-328 (2009).
42. Desgrosellier JS, Cheresh DA. Integrins in cancer: Biological implications and therapeutic opportunities. Nat. Rev. Cancer 10(1), 9-22 (2010). Review of integrins in cancer biology and anti-integrins in therapeutic development.
43. Baker EL, Zaman MH. The biomechanical integrin. J. Biomechanics 43(1), 38-44 (2010).
44. Jin H, Aiyer A, Su J. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J. Clin. Invest. 116(3), 652-662 (2006). (Pubitemid 43326874)
45. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat. Rev. Cancer 8(8), 604-617 (2008).
46. Garmy-Susini B, Jin H, Zhu Y, Sung RJ, Hwang R, Varner J. Integrin a4b1-VCAM- 1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J. Clin. Invest. 115(6), 1542-1551 (2005). (Pubitemid 40814662)
47. 3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res. 62(10), 2824-2833 (2002). (Pubitemid 34525767)
48. 5 integrin expression in glioma periphery. Neurosurgery 49(2), 380-389 (2001).
49. 3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol. 18(3), 378-386 (2008). (Pubitemid 351782847)
50. Paulus W, Baur I, Schuppan D, Roggwendorf W. Characterization of integrin receptors in normal and neoplastic human brain. Am. J. Pathol. 143, 154-163 (1993). (Pubitemid 24058169)
51. Rutka JT, Muller M, Hubbard SL et al. Astrocytoma adhesion to extracellular matrix: Functional significance of integrin and focal adhesion kinase expression. J. Neuropathol. Exp. Neurol. 58(2), 198-209 (1999). (Pubitemid 29088943)
52. Belot N, Rorive S, Doyen I et al. Molecular characterization of cell substratum attachments in human glial tumors relates to prognostic features. Glia 36(3), 375-390 (2001). (Pubitemid 34010065)
53. vintegrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int. J. Cancer 98(5), 690-697 (2002). (Pubitemid 34228889)
54. Galli R, Binda E, Orfanelli U. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioglastoma. Cancer Res. 64(11), 7011-7021 (2004). (Pubitemid 39331011)
55. Singh SK, Hawkins C, Clarke ID. Identification of human brain tumour initiating cells. Nature 432(7015), 396-401 (2004). (Pubitemid 39551674)
56. Schmalz PGR, Shen MJ, Park JK. Treatment resistance mechanisms of malignant glioma tumor stem cells. Cancers 3(1), 621-635 (2011).
57. Li Z, Wang H, Eyler CE, Hjelmeland AB, Rich JN. Turning cancer stem cells inside out: An exploration of glioma stem cell signaling pathways. J. Biol. Chem. 284(25), 16705-16709 (2009).
58. 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5), 421-432 (2010).
59. 5 integrins-FAK-RhoB: A novel pathway for hypoxia regulation in glioblastoma. Cancer Res. 69(8), 3308-3316 (2009).
60. Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro. Oncol. 7(2), 134-153 (2005). (Pubitemid 40590514)
61. Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11(3), 293-299 (2001). (Pubitemid 32480296)
62. Semenza GL. HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol. 88(4), 1474-1480 (2000). (Pubitemid 30217451)
63. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway. J. Clin. Oncol. 23(5), 1011-1027 (2005).
64. Millard M, Odde S, Neamati N. Integrin targeted therapeutics. Theranostics 1, 154-188 (2011).
65. Abdollahi A, Lipson KE, Sckell A et al. Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res. 63(24), 8890-8898 (2003). (Pubitemid 38064069)
66. 3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion. Clin. Cancer Res. 11(21), 7851-7860 (2005). (Pubitemid 41611630)
67. V integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin. Cancer Res. 13(7), 2128-2135 (2007). (Pubitemid 46649882)
68. Ricart AD, Tolcher AW, Liu G et al. Volociximab, a chimeric monoclonal antibody that specifically binds a5b1 integrin: A Phase 1, pharmacokinetic, and biological correlative study. Clin. Cancer Res. 14(23), 7924-7929 (2008).
69. Mas-Moruno C, Rechenmacher F, Kessler H. Cilengitide: The first anti-angiogenic small molecule drug candidate. Design, synthesis and clinical evaluation. Anticancer Agents Med. Chem. 10(10), 753-768 (2010).
70. Loges S, Butzal M, Otten J. Cilengitide inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Biochem. Biophys. Res. Commun. 357(4), 1016-1020 (2007). (Pubitemid 46695889)
71. 3 antagonist cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small cell lung cancer models. Int. J. Radiat. Oncol. Biol. Phys. 65(5), 1536-1543 (2006). (Pubitemid 44425239)
72. Mikkelsen T, Brodie C, Finniss S et al. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int. J. Cancer 124(11), 2719-2727 (2009).
73. Reynolds AR, Hart IR, Watson AR et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med. 15(4), 392-400 (2009).
74. 3 integrin antagonists. J. Med. Chem. 42(16), 3033-3040 (1999). (Pubitemid 29384038)
75. 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 6(2), 105-119 (2003). (Pubitemid 38173862)
76. 3. Science 296(5565), 151-155 (2002). (Pubitemid 34280076)
77. V integrins. Science 270(5241), 1500-1502 (1995). (Pubitemid 3005294)
78. Hammes HP, Brownlee M, Jonczyk A, Sutter A, Preissner KT. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat. Med. 2(5), 529-533 (1996). (Pubitemid 26151516)
79. Yamada S, Bu XY, Khankaldyyan V, Gonzales-Gomez I, McComb JG, Laug WE. Effect of the angiogenesis inhibitor cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery 59(6), 1304-1312 (2006). (Pubitemid 44949775)
80. Tentori L, Dorio AS, Muzi A et al. The integrin antagonist cilengitide increases the antitumor activity of temozolomide against malignant melanoma. Oncol. Rep. 19(4), 1039-1043 (2008). (Pubitemid 351802678)
81. V antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases. Proc. Natl Acad. Sci. 96(4), 1591-1596 (1999). (Pubitemid 29098496)
82. 5 in patients with advanced solid tumours. Eur. J. Cancer 39(7), 917-926 (2003). (Pubitemid 36428623)
83. Nabors LB, Mikkelsen T, Rosenfeld SS et al. Phase 1 and correlative biology study of cilengitide in patients with recurrent malignant glioma. J. Clin. Oncol. 25(13), 1651-1657 (2007). The first Phase I study of cilengitide in recurrent gliomas attesting to the safety of infusional cilengitide. (Pubitemid 46797943)
84. MacDonald TJ, Stewart CF, Kocak M et al. Phase 1 clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium study PBTC-012. J. Clin. Oncol. 26(6), 919-924 (2008). (Pubitemid 351398085)
85. Lam MSH, Ignoffo RJ. A guide to clinically relevant drug interactions in oncology. J. Oncol. Pharm. Pract. 9, 45-85 (2003). (Pubitemid 37051478)
86. Rubenstein JL, Kim J, Ozawa T et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2(4), 306-314 (2000).
87. Batchelor TT, Duda DG, di Tomaso E et al. Phase 2 study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28(17), 2817-2823 (2010).
88. Reardon DA, Fink KL, Mikkelsen T et al. Randomized Phase 2 study of cilengitide, an integrin-targeting arginine-lysine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 26(34), 5610-5617 (2008). The first Phase II study of cilengitide for recurrent GBM.
89. Fink K, Mikkelsen T, Nabors LB et al. Long-term effects of cilengitide, a novel integrin inhibitor, in recurrent glioblastoma: A randomized Phase 2a study. J. Clin. Oncol. 28(Suppl. 15) (2010) (Abstract 2010).
90. Gilbert M, Lamborn K, Lassman AB et al. Tumor tissue delivery of cilengitide after intravenous administration to patients with recurrent glioblastoma (GBM): Preliminary data from NABTC protocol 03-02. Presented at: The 12th Annual Meeting of the Society for Neuro-Oncology. Dallas, TX, USA, 15-18 November 2007.
91. Stupp R, Hegi ME, Neyns B et al. Phase 1/2a study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28(16), 2712-2718 (2010).
92. Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352(10), 997-1003 (2005). (Pubitemid 40349502)
93. Verhaak RGW, Hoadley KA, Purdom E et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1), 98-110 (2010).
94. Nabors LB, Mikkelsen T, Batchelor T et al. NABTT 0306: A randomized Phase 2 trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM). J. Clin. Oncol. 27, S15 (2009) (Abstract 2001).
95. Franceschi E, Tosoni A, Bartolini S, Mazzocchi V, Fioravanti A, Brandes AA. Treatment options for recurrent glioblastoma: Pitfalls and future trends. Expert Rev. Anticancer Ther. 9(5), 613-619 (2009).
96. Galanis E, Buckner JC, Maurer MJ et al. Phase 2 trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment group study. J. Clin. Oncol. 23(23), 5294-5304 (2005). (Pubitemid 46206983)
97. Stupp R, Van Den Bent J, Erridge SC et al. Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: Protocol of a multicenter, randomized, open-label, controlled Phase 2 trial (CENTRIC). J. Clin. Oncol. 28(Suppl. 15) (2010) (Abstract TPS152). Phase II study that resulted in the design and completion of the CENTRIC randomized Phase III trial of cilengitide for newly diagnosed GBM.
98. Grossman SA, Ye X, Chamberlain M et al. Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: A multicenter Phase 2 trial. J. Clin. Oncol. 27(25), 4155-4161 (2009).
99. Rosenfeld MR, Chamberlain MC, Grossman SA et al. A multi-institution Phase 2 study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro. Oncol. 12(10), 1071-1077 (2010).
100. Avastin®, package insert. Genentech, Inc., CA, USA (2011).