Selective VEGFR inhibitors for anticancer therapeutics in clinical use and clinical trials

Current Pharmaceutical Design

Volumn 18, Issue 20, 2012, Pages 2921-2935

  Zhang, Cunlong ^a   Tan, Chunyan ^a   Ding, Huaiwei ^a   Xin, Tian ^a   Jiang, Yuyang ^a,b  

^a TSINGHUA UNIVERSITY   (China)

^b Tsinghua University   (China)

Author keywords

Angiogenesis; Anticancer; Selective; VEGFR inhibitor

Indexed keywords

5 [(5 FLUORO 1,2 DIHYDRO 2 OXO 3H INDOL 3 YLIDENE)METHYL] N (2 HYDROXY 3 MORPHOLINOPROPYL) 2,4 DIMETHYL 1H PYRROLE 3 CARBOXAMIDE; APATINIB; AXITINIB; BAY 579352; BRIVANIB ALANINATE; CARBOPLATIN; CEDIRANIB; CETUXIMAB; DOCETAXEL; DOVITINIB; ERLOTINIB; FLUOROURACIL; GEMCITABINE; LENVATINIB; LINIFANIB; MOTESANIB; NINTEDANIB; OSI 930; PACLITAXEL; PAZOPANIB; PEMETREXED; REGORAFENIB; SORAFENIB; SUNITINIB; TELATINIB; TIVOZANIB; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR INHIBITOR; VASCULOTROPIN; VASCULOTROPIN RECEPTOR; VATALANIB; YN 968D1;

ACUTE GRANULOCYTIC LEUKEMIA; ALKALINE PHOSPHATASE BLOOD LEVEL; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BREAST CANCER; BREAST METASTASIS; CANCER CHEMOTHERAPY; CANCER SURVIVAL; CARDIOTOXICITY; CASTRATION RESISTANT PROSTATE CANCER; COLORECTAL CANCER; CONTINUOUS INFUSION; DEATH; DECREASED APPETITE; DIARRHEA; DIFFERENTIATED THYROID CANCER; DIGESTIVE SYSTEM CANCER; DIGESTIVE SYSTEM FISTULA; DIGESTIVE SYSTEM PERFORATION; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG RESPONSE; DRUG SELECTIVITY; DYSPHONIA; EDEMA; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; GASTROINTESTINAL SYMPTOM; GLIOBLASTOMA; GYNECOLOGIC CANCER; HAIR DISCOLORATION; HAND FOOT SYNDROME; HEADACHE; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERTENSION; HYPOPHOSPHATEMIA; KIDNEY CARCINOMA; LEWIS CARCINOMA; LIVER CELL CARCINOMA; LOADING DRUG DOSE; LUNG METASTASIS; LUNG NON SMALL CELL CANCER; MELANOMA; METASTATIC MELANOMA; MOUTH PAIN; MULTIPLE CYCLE TREATMENT; NAUSEA; NONHUMAN; OVARY CANCER; PANCREAS CANCER; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEINURIA; QT PROLONGATION; RECOMMENDED DRUG DOSE; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SILENT MYOCARDIAL INFARCTION; SKIN DISCOLORATION; SKIN DISEASE; SOLID TUMOR; STOMACH CANCER; STOMATITIS; STROKE; THROMBOCYTOPENIA; THYROID CANCER; THYROID MEDULLARY CARCINOMA; TORSADE DES POINTES; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; VOMITING; WEIGHT REDUCTION; YELLOW COLORATION OF THE SKIN;

EID: 84861733219     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212800672732     Document Type: Review

References (179)

1. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nat 2000; 407: 249-57.
2. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clinical Oncol 2009; 6: 569-79.
3. Figg WD, Cook KM. Angiogenesis Inhibitors: Current Strategies and Future Prospects. Ca-a Cancer J for Clinicians 2010; 60: 222-43.
4. Folkman J. Is angiogenesis an organizing principle in biology and medicine? J Pediatric Surgery 2007; 42: 1-11.
5. Jain RK. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 2005; 307: 58-62.
6. Laquente B, Vinals F, Germa JR. Metronomic chemotherapy: an antiangiogenic scheduling. Clinical Translational Oncol 2007; 9: 93-8.
7. Perrone F, Morabito A, De Maio E, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: Current status and future directions. Oncologist 2006; 11: 753-64.
8. Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Current Oncol Reports 2007; 9: 115-9.
9. Muller YA, Li B, Christinger HW, et al. Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site. Proce Nat Acad Sci USA 1997; 94: 7192-7.
10. Shibuya M. Vascular endothelial growth factor-dependent and-independent regulation of angiogenesis. Bmb Reports 2008; 41: 278-86.
11. Cui TG, Foster RR, Saleem M, et al. Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF(165)b) mRNA and protein. Am J Physiol-Renal Physiol 2004; 286: F767-73.
12. Ferrara N, DavisSmyth T. The biology of vascular endothelial growth factor. Endocrine Rev 1997; 18: 4-25.
13. Shibuya M. Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Structure and Function 2001; 26: 25-35.
14. Ferrara N, CarverMoore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nat 1996; 380: 439-42.
15. Aiello LP, Avery RL, Arrigg PG, et al. Vascular Endothelial Growth-Factor in Ocular Fluid of Patients with Diabetic-Retinopathy and Other Retinal Disorders. New Eng J Med 1994; 331: 1480-7.
16. Shibuya M, Takahashi T, Yamaguchi S, Chida K. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. Embo J 2001; 20: 2768-78.
17. Keyt BA, Nguyen HV, Berleau LT, et al. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors-Generation of receptor-selective VEGF variants by sitedirected mutagenesis. J Biol Chem 1996; 271: 5638-46.
18. Shinkai A, Ito M, Anazawa H, et al. Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor. J Biol Chem 1998; 273: 31283-8.
19. Neufeld G, Cohen T, Shraga N, et al. The neuropilins: Multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovascular Med 2002; 12: 13-9.
20. Rahimi N. VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Frontiers in Bioscience 2006; 11: 818-29.
21. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002; 1: 219-27.
22. Kopfstein L, Veikkola T, Djonov VG, et al. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol 2007; 170: 1348-61.
23. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 Receptor Tyrosine Kinase in Regulating the Assembly of Vascular Endothelium. Nat 1995; 376: 66-70.
24. Roberts DM, Kearney JB, Johnson JH, et al. The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol 2004; 164: 1531-5.
25. Lohela M, Saaristo A, Veikkola T, Alitalo K. Lymphangiogenic growth factors, receptors and therapies. Thrombosis and Haemostasis 2003; 90: 167-84.
26. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: Therapeutic perspective. Clinical Cancer Res 2006; 12: 5018-22.
27. Xu D, Wang TL, Sun LP, You QD. Recent Progress of Small Molecular VEGFR Inhibitors as Anticancer Agents. Mini-Rev Med Chem 2011; 11: 18-31.
28. Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cellular Signalling 2007; 19: 2003-12.
29. Groopman JE, Wang JF, Zhang XF. Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. J Biol Chem 2004; 279: 27088-97.
30. Dayanir V, Meyer RD, Lashkari K, Rahimi N. Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. J Biol Chem 2001; 276: 17686-92.
31. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nat 2001; 411: 355-65.
32. Lamalice L, Houle F, Jourdan G, Huot J. Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38. Oncogene 2004; 23: 434-45.
33. Rousseau S, Houle F, Landry J, Huot J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 1997; 15: 2169-77.
34. Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome. Science 2002; 298: 1912-+.
35. Veeravagu A, Hsu AR, Cai WB, et al. Vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors as anti-angiogenic agents in cancer therapy. Recent Patents on Anti-Cancer Drug Discov 2007; 2: 59-71.
36. Wells SA, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clinical Oncol 2010; 28: 767.
37. Baudin E, Schlumberger M. New therapeutic approaches for metastatic thyroid carcinoma. Lancet Oncol 2007; 8: 148-56.
38. Tonra JR, Deevi DS, Corcoran E, et al. Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clinical Cancer Res 2006; 12: 2197-207.
39. Li YA, Yang XP, Sui LJ, Flaig TW. VEGFR and EGFR inhibition increases epithelial cellular characteristics and chemotherapy sensitivity in mesenchymal bladder cancer cells. Oncol Reports 2010; 24: 1019-28.
40. Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist 2011; 16: 432-44.
41. Blanchet B, Billemont B, Barete S, et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf 2010; 9: 275-87.
42. Arao T, Matsumoto K, Furuta K, et al. Acquired Drug Resistance to Vascular Endothelial Growth Factor Receptor 2 Tyrosine Kinase Inhibitor in Human Vascular Endothelial Cells. Anticancer Res 2011; 31: 2787-96.
43. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discovery 2006; 5: 835-44.
44. Wilhelm SM, Carter C, Tang LY, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-109.
45. Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov 2006; 5: 993-6.
46. Sharma A, Trivedi NR, Zimmerman MA, et al. Mutant V599EBRaf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 2005; 65: 2412-21.
47. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafnib in patients with metastatic renal cell carcinoma. J Clinical Oncol 2006; 24: 2505-12.
48. Escudier B, Szczylik C, Eisen T, et al. Randomized Phase III trial of the multi-kinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Ejc Supplements 2005; 3: 226-6.
49. Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clinical Cancer Res 2006; 12: 7271-8.
50. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clinical Oncol 2005; 23: 965.
51. Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clinical Oncol 2006; 24: 4293-300.
52. Llovet J, Ricci S, Mazzaferro V, et al. Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC). J Clinical Oncol 2007; 25: LBA1.
53. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. New Eng J Med 2008; 359: 378-90.
54. Kamba T, McDonald D. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96: 1788-95.
55. Govindarajan R, Adusumilli J, Baxter DL, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clinical Oncol 2006; 24: e48-8.
56. Matthews DJ, Gerritsen ME. Front Matter. In: Targeting Protein Kinases for Cancer Therapy. John Wiley & Sons, Inc.; 2010. pp. ixiii.
57. Manley PW, Bold G, Bruggen J, et al. Advances in the structural biology, VEGF-R kinase inhibitors for design and clinical development of the treatment of angiogenesis. Biochimica Et Biophysica Acta-Proteins Proteomics 2004; 1697: 17-27.
58. Roskoski R. Sunitinib: A VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophysical Res Communications 2007; 356: 323-8.
59. Mendel DB, Laird AD, Xin XH, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clinical Cancer Res 2003; 9: 327-37.
60. Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734-45.
61. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clinical Oncol 2006; 24: 25-35.
62. Ederhy S, Cohen A, Dufaitre G, et al. QT interval prolongation among patients treated with angiogenesis inhibitors. Targeted Oncol 2009; 4: 89-97.
63. Buckstein R, Meyer RM, Seymour L, et al. Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND. 182-185. Current Oncol 2007; 14: 154.
64. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clinical Oncol 2006; 24: 16-24.
65. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007; 178: 1883-7.
66. Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFNalpha) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clinical Oncol 2006; 24: 930s.
67. Casali PG, Garrett CR, Blackstein ME, et al. Updated results from a phase III trial of sunitinib in GIST patients (pts) for whom imatinib (IM) therapy has failed due to resistance or intolerance. J Clinical Oncol 2006; 24: 523s-523s.
68. Sorbera LA, Bolos J, Serradell N. Pazopanib hydrochloride. Oncolytic, angiogenesis inhibitor, VEGFR-2 tyrosine kinase inhibitor. Drugs of the Future 2006; 31: 585-589.
69. Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 2008; 51: 4632-40.
70. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokineticpharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Molecular Cancer Therapeut 2007; 6: 2012.
71. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokineticpharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Therapeut 2007; 6: 2012-21.
72. Schutz FAB, Choueiri TK, Sternberg CN. Pazopanib: Clinical development of a potent anti-angiogenic drug. Critical Rev Oncol Hematol 2011; 77: 163-71.
73. Hutson TE, Davis ID, Machiels JPH, et al. Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma. J Clinical Oncol 2010; 28: 475-80.
74. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. J Clinical Oncol 2010; 28: 1061-8.
75. Keisner SV, Shah SR. Pazopanib The Newest Tyrosine Kinase Inhibitor for the Treatment of Advanced or Metastatic Renal Cell Carcinoma. Drugs 2011; 71: 443-54.
76. Hennequin LF, Stokes ESE, Thomas AP, et al. Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Medicinal Chem 2002; 45: 1300-12.
77. Ryan AJ, Wedge SR. ZD6474-a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer 2005; 92: S6-S13.
78. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002; 62: 7284-90.
79. Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100 mg) in Patients with Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer. J Clinical Endocrinol Metabol 2010; 95: 2664-71.
80. Wells SA, Robinson BG, Gagel RF, et al. Vandetanib in Locally Advanced or Metastatic Medullary Thyroid Cancer (Mtc): A Randomized, Double-Blind Phase Iii Trial (Zeta). Annals Oncol 2010; 21: 315.
81. Gild ML, Bullock M, Robinson BG, Clifton-Bligh R. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinology 2011; 7: 617-24.
82. Deshpande H, Roman S, Thumar J, Sosa JA. Vandetanib (ZD6474) in the Treatment of Medullary Thyroid cancer. Clinical Med Insights. Oncol 2011; 5: 213.
83. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis (vol 43, pg 2316, 2000). J Med Chem 2000; 43: 3200.
84. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000; 43: 2310-23.
85. YUAN K, Sun P, Zhou Y, Chen Y. The salts of N-[4-(1-Cyanocyclopentyl) phenyl]-2-(4-pyridyl methyl) amino-3-pyridine carboxamide. In: WO Patent WO/2010/031,266; 2010.
86. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000; 60: 2178-89.
87. Langenberg MH, Witteveen PO, Lankheet N, et al. Phase I study of combination treatment with PTK 787/ZK 222584 (PTK/ZK) and cetuximab for patients with advanced solid tumors: Safety, pharmacokinetics, pharmacodynamics, and toxicity analysis. J Clinical Oncol 2009; 27.
88. Joensuu H, De Braud F, Coco P, et al. Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate. Annals Oncol 2008; 19: 173-7.
89. Cook N, Basu B, Biswas S, et al. A phase 2 study of vatalanib in metastatic melanoma patients. Eur J Cancer 2010; 46: 2671-3.
90. Los M, Roodhart JML, Voest EE. Target practice: Lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007; 12: 443-50.
91. Zhong HZ, Bowen JP. Recent Advances in Small Molecule Inhibitors of VEGFR and EGFR Signaling Pathways. Curr Topics Med Chem 2011; 11: 1571-90.
92. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical Antiangiogenesis and Antitumor Activities of Axitinib (AG-013736), an Oral, Potent, and Selective Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases 1, 2, 3. Clinical Cancer Res 2008; 14: 7272-83.
93. Sharma S, Abhyankar V, Burgess RE, et al. A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Annals Oncol 2010; 21: 297-304.
94. Kiselyov A, Balakin KV, Tkachenko SE. VEGF/VEGFR signalling as a target for inhibiting angiogenesis. 2007.
95. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: Pharmacokinetic and clinical results. J Clinical Oncol 2005; 23: 5474-83.
96. Rixe O, Meric JB, Bloch J, et al. Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC). J Clinical Oncol 2005; 23: 192s.
97. Spano JP, Chodkiewicz C, Maurel J, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 2008; 371: 2101-8.
98. Rugo H, Stopeck A, Joy A, et al. A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC). J Clinical Oncol 2007; 25: 1003.
99. Cohen EEW, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clinical Oncol 2008; 26: 4708-13.
100. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 2005; 65: 4389-400.
101. Yamamoto N, Tamura T, Yamamoto N, et al. Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN (TM), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemotherapy Pharmacol 2009; 64: 1165-72.
102. Fiedler W, Mesters R, Heuser M, et al. An open-label, Phase I study of cediranib (RECENTIN (TM) in patients with acute myeloid leukemia. Leukemia Res 2010; 34: 196-202.
103. Laurie SA, Gauthier I, Arnold A, et al. Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: The National Cancer Institute of Canada clinical trials group. J Clinical Oncol 2008; 26: 1871.
104. Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006; 66: 8715-21.
105. Rosen LS, Kurzrock R, Mulay M, et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clinical Oncol 2007; 25: 2369-76.
106. Kotasek D, Tebbutt N, Welch S, et al. Safety and Pharmacokinetics (Pk) of Motesanib Diphosphate in Combination with Gemcitabine and Erlotinib for the Treatment of Solid Tumors. Annals Oncol 2008; 19: 159-60.
107. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. New Eng J Med 2008; 359: 31-42.
108. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer. J Clinical Oncol 2009; 27: 3794-801.
109. Roth GJ, Heckel A, Colbatzky F, et al. Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120). J Med Chem 2009; 52: 4466-80.
110. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774-82.
111. Du Bois A, Huober J, Stopfer P, et al. A phase I open-label doseescalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Annals of Oncol 2010; 21: 370.
112. Ellis PM, Kaiser R, Zhao Y, et al. Phase I Open-Label Study of Continuous Treatment with BIBF 1120, a Triple Angiokinase Inhibitor, and Pemetrexed in Pretreated Non-Small Cell Lung Cancer Patients. Clinical Cancer Res 2010; 16: 2881.
113. Ledermann JA, Hackshaw A, Kaye S, et al. Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer. J Clinical Oncol 2011; 29: 3798-804.
114. Reck M, Kaiser R, Eschbach C, et al. A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Annals of Oncol 2011; 22: 1374-81.
115. Campas C, Bolos J, Castaner R. TIVOZANIB VEGFR Tyrosine Kinase Inhibitor Angiogenesis Inhibitor Oncolytic. Drugs of the Future 2009; 34: 793-6.
116. Bhargava P, Esteves B, Nosov DA, et al. Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). J Clinical Oncol 2009; 27.
117. Eskens FALM, de Jonge MJA, Van Doorn L, et al. Phase I and pharmacological study of KRN951, a potent VEGFR tyrosine kinase inhibitor given in a 4 week on, 2 week off schedule in patients with advanced solid tumors. Ejc Supplements 2006; 4: 16.
118. Yamaguchi R, Niwakawa M, Onozawa Y, et al. Phase I Study for Krn951 (Av-951), a Selective Vegfr Receptor 1, 2, 3 Tyrosine Kinase Inhibitor in Japanese Patients with Metastatic Solid Tumors. Annals of Oncol 2010; 21: 167-8.
119. De Luca A, Normanno N. Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors (vol 13, pg 636, 2010). Idrugs 2010; 13: 742-2.
120. Dai YJ, Hartandi K, Ji ZQ, et al. Discovery of N-(4-(3-amino-1Hindazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem 2007; 50: 1584-97.
121. Goh BC, Thng CH, Sukri N, et al. Phase I study of ABT869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. Ejc Supplements 2006; 4: 36.
122. Tannir N, Wong Y, Kollmannsberger C, et al. Phase 2 results of ABT-869 treatment in patients with advanced renal cell cancer (RCC) after sunitinib failure. Ejc Supplements 2009; 7: 425.
123. Tan E, Goss G, Salgia RR, et al. Phase II results of ABT-869 treatment in patients with non small cell lung cancer (NSCLC). Ejc Supplements 2009; 7: 509-10.
124. Trudel S, Li ZH, Wei E, et al. CHIR258, a novel multi-targeted tyrosine kinase inhibitor, for the treatment of t(4; 14) multiple myeloma. Blood 2004; 104: 185a.
125. de Menezes DEL, Peng J, Garrett EN, et al. CHIR-258: A potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clinical Cancer Res 2005; 11: 5281-91.
126. Sarker D, Molife R, Evans TRJ, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clinical Cancer Res 2008; 14: 2075-81.
127. Angevin E, Lopez J, Pande A, et al. TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study. J Clinical Oncol 2009; 27.
128. Angevin E, Lin C, Pande A, et al. A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: phase I results. J Clin Oncol 2010; 28: 3057.
129. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011; 129: 245-55.
130. Furuse J, Sasaki Y, Okusaka T, et al. Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of the Multikinase Inhibitor Regorafenib (BAY 73-4506) in Japanese Patients With Advanced Solid Tumours. Eur J Cancer 2011; 47: S155.
131. Eisen T, Joensuu H, Nathan P, et al. Phase II Trial of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as First-line Therapy in Patients With Metastatic or Unresectable Renal Cell Carcinoma (RCC). Eur J Cancer 2011; 47: S517.
132. Bolondi L, Tak WY, Gasbarrini A, et al. Phase II Safety Study of the Oral Multikinase Inhibitor Regorafenib (BAY 73-4506) as Second-line Therapy in Patients With Hepatocellular Carcinoma. Eur J Cancer 2011; 47: S464.
133. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008; 122: 664-71.
134. Yamada K, Yamamoto N, Yamada Y, et al. Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors. Clinical Cancer Res 2011; 17: 2528-37.
135. Sherman S. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). J Clin Oncol 2011; 29: a5503.
136. Tian S, Quan HT, Xie CY, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011; 102: 1374-80.
137. Li J, Zhao XM, Chen L, et al. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. Bmc Cancer 2010; 10.
138. Cai ZW, Zhang Y, Borzilleri RM, et al. Discovery of brivanib alaninate (S)-(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215). J Med Chem 2008; 51: 1976-80.
139. Garrett CR, Siu LL, El-Khoueiry A, et al. Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with fulldose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy. Br J Cancer 2011; 105: 44-52.
140. Park JW, Finn RS, Kim JS, et al. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clinical Cancer Res 2011; 17: 1973.
141. Strumberg D, Schultheis B, Adamietz IA, et al. Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours. Br J Cancer 2008; 99: 1579-85.
142. Gelderblom H, Verweij J, Steeghs N, et al. Phase I, safety, pharmacokinetic and biomarker study of telatinib (BAY 57-9352), an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors. Ejc Supplements 2006; 4: 26-6.
143. Eskens FALM, Steeghs N, Verweij J, et al. Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor beta, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors. J Clinical Oncol 2009; 27: 4169-76.
144. Langenberg MHG, Witteveen PO, Roodhart JM, et al. Phase I Evaluation of Telatinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Combination with Irinotecan and Capecitabine in Patients with Advanced Solid Tumors. Clinical Cancer Res 2010; 16: 2187-97.
145. Alsina M, Ajani JA, Ko AH, et al. Phase 2 Study of Telatinib in Combination with Capecitabine and Cisplatin as First-Line Treatment in Patients with Advanced Cancer of the Stomach or Gastro-Esophageal Junction (Gej). Annals Oncol 2010; 21: 229.
146. Patyna S, Laird AD, Mendel DB, et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol Cancer Therapeut 2006; 5: 1774-82.
147. Fiedler W, Giaccone G, Lasch P, et al. Phase I trial of SU14813 in patients with advanced solid malignancies. Annals Oncol 2011; 22: 195-201.
148. Garton AJ, Crew APA, Franklin M, et al. OSI-930: A novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res 2006; 66: 1015-24.
149. George S, Lal R, Camidge DR, et al. Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors. J Clinical Oncol 2009; 27.
150. Macpherson I, Stewart K, Chick J, et al. A dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of OSI-930 and erlotinib (E) in patients (pts) with advanced solid tumors. J Clinical Oncol 2009; 27.
151. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592-603.
152. Duda DG, Ancukiewicz M, Jain RK. Biomarkers of antiangiogenic therapy: how do we move from candidate biomarkers to valid biomarkers? J Clin Oncol 2010; 28: 183-5.
153. Deprimo SE, Bello CL, Smeraglia J, et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med 2007; 5: 32.
154. La Thangue NB, Kerr DJ. Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clinical Oncol 2011; 8: 587-96.
155. Beckman RA, Clark J, Chen C. Integrating predictive biomarkers and classifiers into oncology clinical development programmes. Nat Rev Drug Discov 2011; 10: 735-48.
156. Rusnati M, Camozzi M, Moroni E, et al. Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis. Blood 2004; 104: 92-9.
157. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007; 131: 463-75.
158. Fernando NT, Koch M, Rothrock C, et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 2008; 14: 1529-39.
159. Chae SS, Kamoun WS, Farrar CT, et al. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res 2010; 16: 3618-27.
160. Zijlmans HJ, Fleuren GJ, Hazelbag S, et al. Expression of endoglin (CD105) in cervical cancer. Br J Cancer 2009; 100: 1617-26.
161. Kojima T, Chang JH, Azar DT. Proangiogenic role of ephrinB1/EphB1 in basic fibroblast growth factor-induced corneal angiogenesis. Am J Pathol 2007; 170: 764-73.
162. Trebec-Reynolds DP, Voronov I, Heersche JN, Manolson MF. VEGF-A expression in osteoclasts is regulated by NF-kappaB induction of HIF-1alpha. J Cellular BioChem 2010; 110: 343-51.
163. Bello E, Colella G, Scarlato V, et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res 2011; 71: 1396-405.
164. Jonker DJ, Rosen LS, Sawyer MB, et al. A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann Oncol 2011; 22: 1413-9.
165. Rennel ES, Regula JT, Harper SJ, et al. A human neutralizing antibody specific to Ang-2 inhibits ocular angiogenesis. Microcirculation 2011; 18: 598-607.
166. Seon BK, Haba A, Matsuno F, et al. Endoglin-targeted cancer therapy. Curr Drug Deliv 2011; 8: 135-43.
167. Farrar CT, Kamoun WS, Ley CD, et al. Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model. Plos One 2011; 6: e17228.
168. Mross K, Fasol U, Frost A, et al. DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study. J Angiogenes Res 2009; 1: 5.
169. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592-603.
170. Thakker GD, Hajjar DP, Muller WA, Rosengart TK. The role of phosphatidylinositol 3-kinase in vascular endothelial growth factor signaling. J Biol Chem 1999; 274: 10002-7.
171. Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004; 90: 2-8.
172. Jia J, Zhu F, Ma XH, et al. Mechanisms of drug combinations: interaction and network perspectives (vol 8, pg 111, 2009). Nat Rev Drug Discovery 2009; 8.
173. Sawyers CL. Cancer-Mixing cocktails. Nat 2007; 449: 993-6.
174. Pratilas CA, Solit DB. Targeting the Mitogen-Activated Protein Kinase Pathway: Physiological Feedback and Drug Response. Clinical Cancer Res 2010; 16: 3329-34.
175. Tan DSW, Gerlinger M, Teh BT, Swanton C. Anti-cancer drug resistance: Understanding the mechanisms through the use of integrative genomics and functional RNA interference. Eur J Cancer 2010; 46: 2166-77.
176. Biankin AV, Hudson TJ. Somatic variation and cancer: therapies lost in the mix. Human Genetics 2011; 130: 79-91.
177. Bukowski RM. Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma. Expert Review of Anticancer Therapy 2010; 10: 635-45.
178. O'Connor JPB, Jackson A, Parker GJM, Jayson GC. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. British J Cancer 2007; 96: 189-95.
179. di Tomaso E, London N, Fuja D, et al. PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment. Plos One 2009; 4.