Advances in malignant glioma drug discovery

Expert Opinion on Drug Discovery

Volumn 6, Issue 7, 2011, Pages 739-753

  Reardon, David A ^a   Perry, James R ^b   Brandes, Alba A ^c   Jalali, Rakesh ^d   Wick, Wolfgang ^e  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF TORONTO   (Canada)

^c BELLARIA HOSPITAL   (Italy)

^d TATA MEMORIAL HOSPITAL   (India)

^e UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Angiogenesis; EGFR; glioblastoma; integrins; malignant glioma; temozolomide

Indexed keywords

AFATINIB; AFLIBERCEPT; BEVACIZUMAB; BEVACIZUMAB PLUS IRINOTECAN; CEDIRANIB; CETUXIMAB; CILENGITIDE; DACOMITINIB; ERLOTINIB; ETOPOSIDE; GEFITINIB; IRINOTECAN; LENVATINIB; LOMUSTINE; PAZOPANIB; SUNITINIB; TEMOZOLOMIDE; UNCLASSIFIED DRUG; VANDETANIB; VISMODEGIB; XL 184; XL 765;

ADD ON THERAPY; BONE MARROW SUPPRESSION; BRAIN ISCHEMIA; CANCER RADIOTHERAPY; CANCER SURGERY; CANCER SURVIVAL; CLINICAL EFFECTIVENESS; COLORECTAL CANCER; CRANIOTOMY; DRUG EFFICACY; DRUG SAFETY; ENZYME ACTIVITY; FATIGUE; FOLLOW UP; GENE AMPLIFICATION; GLIOBLASTOMA; HAND FOOT SYNDROME; HEAD AND NECK CANCER; HUMAN; HYPERTENSION; LUNG NON SMALL CELL CANCER; LYMPHOCYTOPENIA; MEDULLOBLASTOMA; MULTICENTER STUDY (TOPIC); MULTIPLE CYCLE TREATMENT; NEUTROPENIA; OPPORTUNISTIC INFECTION; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEINURIA; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENT CANCER; RETROSPECTIVE STUDY; REVIEW; STEREOTACTIC RADIOSURGERY; SYSTEMIC HEMORRHAGE; THROMBOCYTOPENIA; THROMBOSIS;

EID: 79959486853     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2011.584530     Document Type: Review

References (209)

1. Jemal A, Siegel R, Xu J, et al. Cancer statistics. CA Cancer J Clin 2010;60(5):277-300
2. CBTRUS CBTRUS: 2010 Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004-2006; 2010
3. Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central Nervous System. 4th Edition. International Agency for Research on Cancer (IARC), 69008 Lyon, France; 2007
4. Fisher JL, Schwartzbaum JA, Wrensch M, et al. Epidemiology of brain tumors. Neurologic clinics 2007;25(4):867-90 (Pubitemid 47603275)
5. Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002: Cancer Incidence, mortality and Prevalence Worldwide, Version 20 IARC CancerBase No. 5 Lyon, IARCPress; 2004
6. Farrell CJ, Plotkin SR. Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol clin 2007;25(4):925-46 (Pubitemid 47610810)
7. 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 III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10(5):459-66
8. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64(19):6892-9 (Pubitemid 39330996)
9. See SJ, Gilbert MR. Anaplastic astrocytoma: diagnosis, prognosis, and management. Semin Oncol 2004;31(5):618-34 (Pubitemid 39389013)
10. Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 2006;66(20):9852-61 (Pubitemid 44672036)
11. Weller M, Berger H, Hartmann C, et al. Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 2007;13(23):6933-7 (Pubitemid 350276872)
12. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 Phase III randomized trial. J Clin Oncol 2006;24(16):2563-9 (Pubitemid 46630635)
13. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360(8):765-73
14. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997-1003 (Pubitemid 40349502)
15. Wick W, Weller M. Classification and management of anaplastic gliomas. Curr Opin Neurol 2009;22(6):650-6
16. van den Bent MJ, Vogelbaum MA, Wen PY, et al. End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's criteria. J Clin Oncol 2009;27(18):2905-8
17. Ballman KV, Buckner JC, Brown PD, et al. The relationship between six-month progression-free survival and 12-month overall survival end points for Phase II trials in patients with glioblastoma multiforme. Neuro-oncol 2007;9(1):29-38 (Pubitemid 46543486)
18. Lamborn KR, Yung WK, Chang SM, et al. Progression-free survival:an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-oncol 2008;10(2):162-70
19. Reardon DA, Rich JN, Friedman HS, et al. Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 2006;24(8):1253-65 (Pubitemid 46622028)
20. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359(5):492-507
21. 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(25):4189-99
22. Wick W, Weller M, van den Bent M, et al. Bevacizumab and recurrent malignant gliomas: a European perspective. J Clin Oncol 2010;28(12):e188-9; author reply e90-2
23. van den Bent MJ, Dubbink HJ, Sanson M, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951 J Clin Oncol 2009;27(35):5881-6
24. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455(7216):1061-8
25. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321(5897):1807-12
26. Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 2009;30(1):7-11
27. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010;28(14):2348-55
28. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010;28(22):3636-43
29. Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006;9(3):157-73 (Pubitemid 43357943)
30. Verhaak RG, 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 2010;17(1):98-110
31. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010;17(5):510-22
32. Jain RK, di Tomaso E, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8(8):610-22 (Pubitemid 47093931)
33. Reardon DA, Wen PY, Desjardins A, et al. Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy. Expert Opin on Biol Ther 2008;8(4):541-53 (Pubitemid 351570416)
34. Brada M, Hoang-Xuan K, Rampling R, et al. Multicenter Phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 2001;12(2):259-66 (Pubitemid 32223879)
35. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987-96 (Pubitemid 40349501)
36. 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(5):588-93 (Pubitemid 30636298)
37. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter Phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol 1999;17(9):2762-71 (Pubitemid 29415233)
38. Newlands ES, Stevens MF, Wedge SR, et al. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997;23(1):35-61 (Pubitemid 27273454)
39. Portnow J, Badie B, Chen M, et al. The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation. Clin Cancer Res 2009;15(22):7092-8
40. Bower M, Newlands ES, Bleehen NM, et al. Multicentre CRC Phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 1997;40(6):484-8 (Pubitemid 27389289)
41. 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(2):353-7 (Pubitemid 39233451)
42. Everaert E, Neyns B, Joosens E, et al. Temozolomide for the treatment of recurrent supratentorial glioma: results of a compassionate use program in Belgium. J Neurooncol 2004;70(1):37-48 (Pubitemid 39193996)
43. Su YB, Sohn S, Krown SE, et al. Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications.[see comment][erratum appears in J Clin Oncol. 2004 May 15;22(10):2038]. J Clin Oncol 2004;22(4):610-16
44. Schwarzberg AB, Stover EH, Sengupta T, et al. Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide. Cancer Invest 2007;25(4):249-55 (Pubitemid 47026948)
45. Tosoni A, Cavallo G, Ermani M, et al. Is protracted low-dose temozolomide feasible in glioma patients? Neurology 2006;66(3):427-9 (Pubitemid 43739951)
46. Jalali R, Singh P, Menon H, et al. Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide. J Neurooncol 2007;85(1):105-7 (Pubitemid 47422663)
47. Armstrong TS, Cao Y, Scheurer ME, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro-oncology 2009;11(6):825-32
48. Gerber DE, Grossman SA, Zeltzman M, et al. The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas. Neuro-oncology 2007;9(1):47-52 (Pubitemid 46543488)
49. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003;88(7):1004-11 (Pubitemid 36560766)
50. Liu L, Gerson SL. Targeted modulation of MGMT: clinical implications. Clin Cancer Res 2006;12(2):328-31 (Pubitemid 43166117)
51. Wick A, Felsberg J, Steinbach JP, et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 2007;25(22):3357-61 (Pubitemid 47325623)
52. Sarkaria JN, Kitange GJ, James CD, et al. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 2008;14(10):2900-8
53. Neyns B, Tosoni A, Hwu WJ, et al. Dose-dense temozolomide regimens: antitumor activity, toxicity, and immunomodulatory effects. Cancer 2010;116(12):2868-77
54. Kreth S, Thon N, Eigenbrod S, et al. O-Methylguanine-DNA Methyltransferase (MGMT) mRNA Expression Predicts Outcome in Malignant Glioma Independent of MGMT Promoter Methylation. PLoS One 2011;6(2):e17156
55. Franceschi E, Omuro AM, Lassman AB, et al. Salvage temozolomide for prior temozolomide responders. Cancer 2005;104(11):2473-6 (Pubitemid 41691570)
56. Wick A, Pascher C, Wick W, et al. Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol 2009;256(5):734-41
57. Perry JR, Rizek P, Cashman R, et al. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer 2008;113(8):2152-7
58. Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 2010;28(12):2051-7
59. Berrocal A, Perez Segura P, Gil M, et al. Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 2010;96:417-22
60. Kong DS, Lee JI, Kim JH, et al. Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro-oncology 2010;12(3):289-96
61. Abacioglu U, Caglar HB, Yumuk PF, et al. Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma. J Neurooncol 2010 Epub ahead of print
62. Chaudhry IH, O'Donovan DG, Brenchley PE, et al. Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 2001;39(4):409-15 (Pubitemid 32990094)
63. Plate KH, Breier G, Millauer B, et al. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res 1993;53(23):5822-7 (Pubitemid 23360294)
64. Salmaggi A, Eoli M, Frigerio S, et al. Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol 2003;62(3):297-303 (Pubitemid 36591966)
65. Zhou YH, Tan F, Hess KR, et al. The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res 2003;9(9):3369-75 (Pubitemid 37082732)
66. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362(6423):841-4 (Pubitemid 23132159)
67. 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(4):306-14
68. Millauer B, Shawver LK, Plate KH, et al. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 1994;367(6463):576-9
69. Jahnke K, Muldoon LL, Varallyay CG, et al. Bevacizumab and carboplatin ncrease survival and asymptomatic tumor volume in a glioma model. Neuro-oncology 2009;11(2):142-50
70. Lee CG, Heijn M, di Tomaso E, et al. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60(19):5565-70
71. Mathieu V, De Neve N, Le Mercier M, et al. Combining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft model. Neoplasia 2008;10(12):1383-92
72. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3(5):391-400 (Pubitemid 38618122)
73. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335-42 (Pubitemid 38702844)
74. Starks-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. World Federation of Neuro-Oncology Meeting; 5 - 8 May; 2005
75. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13(4):1253-9 (Pubitemid 46424067)
76. Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25(30):4722-9 (Pubitemid 350086473)
77. Desjardins A, Reardon DA, Herndon JE, et al. Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res 2008;14(21):7068-73
78. 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(5):740-5
79. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27(28):4733-40
80. Francesconi AB, Dupre S, Matos M, et al. Carboplatin and etoposide combined with bevacizumab for the treatment of recurrent glioblastoma multiforme. J Clin Neurosci 2010;17(8):970-4
81. Raizer JJ, Grimm S, Chamberlain MC, et al. A Phase II trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 2010;116(22):5297-305
82. Reardon DA, Desjardins A, Vredenburgh JJ, et al. Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a Phase II study. Br J Cancer 2009;101(12):1986-94
83. Sathornsumetee S, Desjardins A, Vredenburgh JJ, et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro-oncology 2010;12(12):1300-10
84. Hasselbalch B, Lassen U, Hansen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a Phase II trial. Neuro-oncology 2010;12(5):508-16
85. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009;75(1):156-63
86. Lai A, Tran A, Nghiemphu PL, et al. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 2011;29(2):142-8
87. Vredenburgh JJ, Desjardins A, Kirkpatrick JP, et al. Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2010 Epub ahead of print
88. Sorensen AG, Batchelor TT, Wen PY, et al. Response criteria for glioma. Nat Clin Pract Oncol 2008;5(11):634-44
89. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28(11):1963-72
90. Quant EC, Norden AD, Drappatz J, et al. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro-oncology 2009;11(5):550-5
91. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99(17):11393-8 (Pubitemid 34920936)
92. Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clinical Colorectal Cancer 2004;4(Suppl 2):S81-5 (Pubitemid 39440148)
93. Gomez-Manzano C, Holash J, Fueyo J, et al. VEGF Trap induces antiglioma effect at different stages of disease. Neuro-oncology 2008;10(6):940-5
94. Wachsberger PR, Burd R, Cardi C, et al. VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys 2007;67(5):1526-37 (Pubitemid 46467151)
95. De Groot JF, Wen PY, Lamborn K, et al. Phase II single arm trial of aflibercept in patients with recurrent temozolomideresistant glioblastoma: NABTC 0601 (Proc Am Soc Clin Oncol abst 2020); ASCO 2008 McCormick Place
96. Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010;28(17):2817-23
97. 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(1):83-95 (Pubitemid 46075199)
98. Batchelor T, Mullholland P, Neyns B, et al. A Phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine along in recurrent glioblastoma patients. Ann Oncol 2010: p. viii4
99. Iwamoto FM, Lamborn KR, Robins HI, et al. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02). Neuro-oncology 2010;12(8):855-61
100. Neyns B, Sadones J, Chaskis C, et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 2010 Epub ahead of print
101. Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 2010;9(10):804-20
102. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10(1):9-22
103. Baker EL, Zaman MH. The biomechanical integrin. J Biomech 2010;43(1):38-44
104. Courter DL, Lomas L, Scatena M, et al. Src kinase activity is required for integrin alphaVbeta3-mediated activation of nuclear factor-kappaB. J Biol Chem 2005;280(13):12145-51
105. Scatena M, Almeida M, Chaisson ML, et al. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 1998;141(4):1083-93 (Pubitemid 28243974)
106. Aoudjit F, Vuori K. Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 2001;20(36):4995-5004 (Pubitemid 32769789)
107. Ricono JM, Huang M, Barnes LA, et al. Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis. Cancer Res 2009;69(4):1383-91
108. Dolfi F, Garcia-Guzman M, Ojaniemi M, et al. The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. Proc Natl Acad Sci USA 1998;95(26):15394-9 (Pubitemid 29018709)
109. Miyamoto S, Teramoto H, Gutkind JS, et al. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol 1996;135(6 Pt 1):1633-42 (Pubitemid 26427657)
110. 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(20):7501-6 (Pubitemid 32995040)
111. Gladson CL, Cheresh DA. Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 1991;88(6):1924-32
112. Schnell O, Krebs B, Wagner E, et al. Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 2008;18(3):378-86 (Pubitemid 351782847)
113. Taga T, Suzuki A, Gonzalez-Gomez I, et al. alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 2002;98(5):690-7 (Pubitemid 34228889)
114. Schnell O, Krebs B, Carlsen J, et al. Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography. Neuro-oncology 2009;11(6):861-70
115. Belot N, Rorive S, Doyen I, et al. Molecular characterization of cell substratum attachments in human glial tumors relates to prognostic features. Glia 2001;36(3):375-90 (Pubitemid 34010065)
116. Vitolo D, Paradiso P, Uccini S, et al. Expression of adhesion molecules and extracellular matrix proteins in glioblastomas: relation to angiogenesis and spread. Histopathology 1996;28(6):521-8 (Pubitemid 26192947)
117. Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol 1999;58(10):1029-40 (Pubitemid 29468264)
118. Gladson CL, Wilcox JN, Sanders L, et al. Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors. J Cell Sci 1995;108 (Pt 3):947-56
119. MacDonald TJ, Taga T, Shimada H, et al. Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 2001;48(1):151-7 (Pubitemid 32039837)
120. Maurer GD, Tritschler I, Adams B, et al. Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro. Neuro-oncology 2009;11(6):747-56
121. Mikkelsen T, Brodie C, Finniss S, et al. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 2009;124(11):2719-27
122. Tentori L, Dorio AS, Muzi A, et al. The integrin antagonist cilengitide increases the antitumor activity of temozolomide against malignant melanoma. Oncol Rep 2008;19(4):1039-43 (Pubitemid 351802678)
123. Yamada S, Bu XY, Khankaldyyan V, et al. Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice.Neurosurgery 2006;59(6):1304-12 (Pubitemid 44949775)
124. Albert JM, Cao C, Geng L, et al. Integrin alpha v beta 3 antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models. Int J Radiat Oncol Biol Phys 2006;65(5):1536-43 (Pubitemid 44425239)
125. Friedlander M, Brooks PC, Shaffer RW, et al. Definition of two angiogenic pathways by distinct alpha v integrins. Science 1995;270(5241):1500-2 (Pubitemid 3005294)
126. Hammes HP, Brownlee M, Jonczyk A, et al. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med 1996;2(5):529-33 (Pubitemid 26151516)
127. Loges S, Butzal M, Otten J, et al. Cilengitide inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Biochem Biophys Res Commun 2007;357(4):1016-20 (Pubitemid 46695889)
128. Nisato RE, Tille JC, Jonczyk A, et al. alphav beta 3 and alphav beta 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 2003;6(2):105-19 (Pubitemid 38173862)
129. 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(34):5610-17
130. Nabors LB, Mikkelsen T, Batchelor T, et al. NABTT 0306: a randomized Phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBMProc Am Soc Clin Oncol 2009 Orlando, FL; 2009 p. 87s
131. 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(13):1651-7 (Pubitemid 46797943)
132. Stupp R, Hegi ME, Neyns B, et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28(16):2712-18
133. MacDonald TJ, Stewart CF, Kocak M, et al. Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012 J Clin Oncol 2008;26(6):919-24 (Pubitemid 351398085)
134. 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 Proc Soc Neuro-Oncol 2007; Dallas, TX; 2007 p. 525
135. Hariharan S, Gustafson D, Holden S, et al. Assessment of the biological and pharmacological effects of the alpha nu beta3 and alpha nu beta5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors. Ann Oncol 2007;18(8):1400-7 (Pubitemid 47305015)
136. Wong H, Bigner SH, Bigner DD, et al. Increased expression of the epidermal growth factor gene in malignant gliomas is invariably related with gene amplification. Proc Natl Acad Sci USA 1987;84:6899-903
137. Watanabe K, Tachibana O, Sata K, et al. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 1996;6(3):217-23
138. Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 1992;89:2965-9
139. Ekstrand AJ, Longo N, Hamid ML, et al. Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene 1994;9(8):2313-20 (Pubitemid 24228682)
140. Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994;91(16):7727-31 (Pubitemid 24238258)
141. 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 2006;12(24):7261-70 (Pubitemid 46095397)
142. Wikstrand CJ, Bigner DD. Prognostic applications of the epidermal growth factor receptor and its ligand, transforming growth factor-alpha. [comment]. J Natl Cancer Inst 1998;90(11):799-801 (Pubitemid 28280540)
143. Shinojima N, Tada K, Shiraishi S, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 2003;63(20):6962-70 (Pubitemid 37322983)
144. Pelloski CE, Lin E, Zhang L, et al. Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res 2006;12(13):3935-41 (Pubitemid 44078078)
145. Sarkaria JN, Yang L, Grogan PT, et al. Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol Cancer Ther 2007;6(3):1167-74 (Pubitemid 46554588)
146. Guillamo JS, de Bouard S, Valable S, et al. Molecular mechanisms underlying effects of epidermal growth factor receptor inhibition on invasion, proliferation, and angiogenesis in experimental glioma. Clin Cancer Res 2009;15(11):3697-704
147. Rich JN, Reardon DA, Peery T, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22(1):133-42 (Pubitemid 41095125)
148. van den Bent MJ, Brandes AA, Rampling R, et al. Randomized Phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034 J Clin Oncol 2009;27(8):1268-74
149. Raizer JJ, Abrey LE, Lassman AB, et al. A Phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro-oncology 2010;12(1):95-103
150. Franceschi E, Cavallo G, Lonardi S, et al. Gefitinib in patients with progressive high-grade gliomas: a multicentre Phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNOBr J Cancer 2007;96(7):1047-51 (Pubitemid 46608313)
151. Lassman AB, Rossi MR, Razier JR, et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from north american brain tumor consortium trials 01-03 and 00-01 Clin Cancer Res 2005;11(21):7841-50 (Pubitemid 41611629)
152. Sathornsumetee S, Reardon DA. Targeting multiple kinases in glioblastoma multiforme. Expert Opin Investig Drugs 2009;18(3):277-92
153. Chang SM, Kuhn J, Lamborn K, et al. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG)(NABTC 04-02Proc Am Soc Clin Oncol 2009 Orlando, FL; 2009 p. 88s
154. Prados M, Gilbert M, Kuhn K, et al. Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM)(NABTC 05-02). Proc Am Soc Clin Oncol 2009 Orlando, FL; 2009 p. 88s
155. Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006;12(3 Pt 1):860-8 (Pubitemid 43259869)
156. Kreisl TN, Lassman AB, Mischel PS, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBMJ Neurooncol 2009;92(1):99-105
157. Doherty L, Gigas DC, Kesari S, et al. Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 2006;67(1):156-8 (Pubitemid 44305484)
158. Brandes AA, Franceschi E, Tosoni A, et al. Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 2008;14(4):957-60 (Pubitemid 351302539)
159. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353(19):2012-24 (Pubitemid 41609094)
160. Haas-Kogan DA, Prados MD, Tihan T, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97(12):880-7 (Pubitemid 41417939)
161. Brown PD, Krishnan S, Sarkaria JN, et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177 J Clin Oncol 2008;26(34):5603-9
162. Uhm JH, Ballman KV, Wu W, et al. Phase II Evaluation of Gefitinib in Patients with Newly Diagnosed Grade 4 Astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074 Int J Radiat Oncol Biol Phys 2011;80:347-53
163. Zwaveling S, Vierboom MP, Ferreira Mota SC, et al. Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells. Cancer Res 2002;62(21):6187-93 (Pubitemid 35244470)
164. Yap TA, Vidal L, Adam J, et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 2010;28(25):3965-72
165. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/ HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27(34):4702-11
166. Bean J, Riely GJ, Balak M, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 2008;14(22):7519-25
167. Gonzales AJ, Hook KE, Althaus IW, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generationirreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther 2008;7(7):1880-9
168. Kelly RJ, Carter C, Giaccone G. Personalizing therapy in an epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer using PF-00299804 and trastuzumab. J Clin Oncol 2010;28(28):e507-10
169. Workman P, Clarke PA, Raynaud FI, et al. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res 2010;70(6):2146-57
170. Castellino RC, Muh CR, Durden DL. PI-3 kinase-PTEN signaling node: an intercept point for the control of angiogenesis. Curr Pharm Des 2009;15(4):380-8
171. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304(5670):554 (Pubitemid 38541907)
172. Gallia GL, Rand V, Siu IM, et al. PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 2006;4(10):709-14 (Pubitemid 44683311)
173. Mizoguchi M, Nutt CL, Mohapatra G, et al. Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol 2004;14(4):372-7 (Pubitemid 39524966)
174. Kita D, Yonekawa Y, Weller M, et al. PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 2007;113(3):295-302 (Pubitemid 46443564)
175. Knobbe CB, Trampe-Kieslich A, Reifenberger G. Genetic alteration and expression of the phosphoinositol-3- kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 2005;31(5):486-90 (Pubitemid 41337782)
176. Hartmann C, Bartels G, Gehlhaar C, et al. PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol 2005;109(6):639-42 (Pubitemid 40974153)
177. Choe G, Horvath S, Cloughesy TF, et al. Analysis of the phosphatidylinositol 3¢-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 2003;63(11):2742-6 (Pubitemid 36667143)
178. Chakravarti A, Zhai G, Suzuki Y, et al. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 2004;22(10):1926-33 (Pubitemid 41095185)
179. Jiang BH, Liu LZ. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 2008;1784(1):150-8
180. Ihle NT, Powis G. Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 2009;8(1):1-9
181. Westhoff MA, Kandenwein JA, Karl S, et al. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene 2009;28(40):3586-96
182. Liu TJ, Koul D, LaFortune T, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 2009;8(8):2204-10
183. Raynaud FI, Eccles SA, Patel S, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941 Mol Cancer Ther 2009;8(7):1725-38
184. Raynaud FI, Eccles S, Clarke PA, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 2007;67(12):5840-50 (Pubitemid 46985018)
185. Opel D, Westhoff MA, Bender A, et al. Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res 2008;68(15):6271-80
186. Chen JS, Zhou LJ, Entin-Meer M, et al. Characterization of structurally distinct, isoform-selective phosphoinositide 3¢-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 2008;7(4):841-50 (Pubitemid 351551037)
187. Kao GD, Jiang Z, Fernandes AM, et al. Inhibition of phosphatidylinositol- 3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 2007;282(29):21206-12 (Pubitemid 47099899)
188. Fan QW, Cheng CK, Nicolaides TP, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 2007;67(17):7960-5 (Pubitemid 47395125)
189. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287(5785):795-801 (Pubitemid 11214475)
190. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008;22(18):2454-72
191. Hooper JE, Scott MP. Communicating with Hedgehogs. Nature Rev 2005;6(4):306-17 (Pubitemid 40516897)
192. Evangelista M, Tian H, de Sauvage FJ. The hedgehog signaling pathway in cancer. Clin Cancer Res 2006;12(20 Pt 1):5924-8 (Pubitemid 44703749)
193. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85(6):841-51 (Pubitemid 26192135)
194. Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Gli1 and the Sonic hedgehog signaling pathway in skin tumours. Nature 1997;389(6653):876-81 (Pubitemid 27462984)
195. Raffel C, Jenkins RB, Frederick L, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res 1997;57(5):842-5 (Pubitemid 27098006)
196. Merchant AA, Matsui W. Targeting Hedgehog-a cancer stem cell pathway. Clin Cancer Res 2010;16(12):3130-40
197. Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007;17(2):165-72 (Pubitemid 46107823)
198. Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007;25(10):2524-33 (Pubitemid 47582744)
199. Ehtesham M, Sarangi A, Valadez JG, et al. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 2007;26(39):5752-61 (Pubitemid 47312811)
200. Becher OJ, Hambardzumyan D, Fomchenko EI, et al. Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res 2008;68(7):2241-9 (Pubitemid 351521797)
201. Shahi MH, Lorente A, Castresana JS. Hedgehog signalling in medulloblastoma, glioblastoma and neuroblastoma. Oncol Rep 2008;19(3):681-8 (Pubitemid 351330436)
202. Duman-Scheel M, Weng L, Xin S, et al. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 2002;417(6886):299-304 (Pubitemid 34534713)
203. Kenney AM, Rowitch DH. Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 2000;20(23):9055-67 (Pubitemid 32245934)
204. Pola R, Ling LE, Silver M, et al. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001;7(6):706-11 (Pubitemid 32588027)
205. Stecca B, Ruiz I, Altaba A. A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. Embo J 2009;28(6):663-76
206. Theunissen JW, de Sauvage FJ. Paracrine Hedgehog signaling in cancer. Cancer Res 2009;69(15):6007-10
207. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455(7211):406-10
208. Xu Q, Yuan X, Liu G, et al. Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 2008;26(12):3018-26
209. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449 N Engl J Med 2009;361(12):1173-8