Building on a foundation of VEGF and mTOR targeted agents in renal cell carcinoma

Biochemical Pharmacology

Volumn 80, Issue 5, 2010, Pages 638-646

  Flaherty, Keith T ^a   Puzanov, Igor ^b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b VANDERBILT INGRAM CANCER CENTER   (United States)

Author keywords

Angiogenesis; HIF; Renal cell carcinoma; VEGF; VHL

Indexed keywords

ANTINEOPLASTIC AGENT; ARQ 197; AXITINIB; BEVACIZUMAB; ERLOTINIB; EVEROLIMUS; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; HYPOXIA INDUCIBLE FACTOR; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MOTESANIB; PAZOPANIB; PHOSPHATIDYLINOSITOL 3 KINASE; SORAFENIB; STAT3 PROTEIN INHIBITOR; SUNITINIB; TEMSIROLIMUS; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN INHIBITOR; VON HIPPEL LINDAU PROTEIN; XL 880;

CANCER COMBINATION CHEMOTHERAPY; CLEAR CELL CARCINOMA; CLINICAL TRIAL; DISEASE MARKER; DRUG DOSE REDUCTION; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG TARGETING; DRUG WITHDRAWAL; GENE DELETION; GENE MUTATION; HEART INFARCTION; HISTOPATHOLOGY; HUMAN; HYPERTENSION; KIDNEY CARCINOMA; KIDNEY FAILURE; METASTASIS; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; NONHUMAN; PAPILLARY CARCINOMA; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEINURIA; REVIEW; SUBCUTANEOUS HEMORRHAGE; THROMBOCYTOPENIA; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; CARCINOMA, RENAL CELL; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; KIDNEY NEOPLASMS; PROTEIN-SERINE-THREONINE KINASES; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 77955684792     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2010.04.005     Document Type: Review

References (111)

1. Kaelin W.G. Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer 2009, 115:2262-2272.
2. Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010;463:360-3.
3. Gordan J.D., Lal P., Dondeti V.R., Letrero R., Parekh K.N., Oquendo C.E., et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 2008, 14:435-446.
4. Ferrara N., Hillan K.J., Gerber H.P., Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004, 3:391-400.
5. Xu L., Tong R., Cochran D.M., Jain R.K. Blocking platelet-derived growth factor-D/platelet-derived growth factor receptor beta signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model. Cancer Res 2005, 65:5711-5719.
6. Cenni E., Perut F., Granchi D., Avnet S., Amato I., Brandi M.L., et al. Inhibition of angiogenesis via FGF-2 blockage in primitive and bone metastatic renal cell carcinoma. Anticancer Res 2007, 27:315-319.
7. Weidner K.M., Sachs M., Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol 1993, 121:145-154.
8. Enholm B., Paavonen K., Ristimaki A., Kumar V., Gunji Y., Klefstrom J., et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997, 14:2475-2483.
9. Gagnon M.L., Bielenberg D.R., Gechtman Z., Miao H.Q., Takashima S., Soker S., et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci U S A 2000, 97:2573-2578.
10. Stein E., Lane A.A., Cerretti D.P., Schoecklmann H.O., Schroff A.D., Van Etten R.L., et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 1998, 12:667-678.
11. Ananth S., Knebelmann B., Gruning W., Dhanabal M., Walz G., Stillman I.E., et al. Transforming growth factor beta1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res 1999, 59:2210-2216.
12. Brugarolas J.B., Vazquez F., Reddy A., Sellers W.R., Kaelin W.G. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003, 4:147-158.
13. Ferrara N., Hillan K.J., Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005, 333:328-335.
14. Maxwell P.H., Pugh C.W., Ratcliffe P.J. Activation of the HIF pathway in cancer. Curr Opin Genet Dev 2001, 11:293-299.
15. Takahashi A., Sasaki H., Kim S.J., Tobisu K., Kakizoe T., Tsukamoto T., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 1994, 54:4233-4237.
16. Yang J.C., Haworth L., Sherry R.M., Hwu P., Schwartzentruber D.J., Topalian S.L., et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003, 349:427-434.
17. Bukowski R.M., Kabbinavar F.F., Figlin R.A., Flaherty K., Srinivas S., Vaishampayan U., et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol 2007, 25:4536-4541.
18. Escudier B., Pluzanska A., Koralewski P., Ravaud A., Bracarda S., Szczylik C., et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007, 370:2103-2111.
19. Gordon M.S., Margolin K., Talpaz M., Sledge G.W., Holmgren E., Benjamin R., et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001, 19:843-850.
20. Veronese M.L., Mosenkis A., Flaherty K.T., Gallagher M., Stevenson J.P., Townsend R.R., et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006, 24:1363-1369.
21. Fukumura D., Gohongi T., Kadambi A., Izumi Y., Ang J., Yun C.O., et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 2001, 98:2604-2609.
22. Schneider B.P., Wang M., Radovich M., Sledge G.W., Badve S., Thor A., et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008, 26:4672-4678.
23. Schneider B.P., Radovich M., Miller K.D. The role of vascular endothelial growth factor genetic variability in cancer. Clin Cancer Res 2009, 15:5297-5302.
24. Badalian G., Derecskei K., Szendroi A., Szendroi M., Timar J. EGFR and VEGFR2 protein expressions in bone metastases of clear cell renal cancer. Anticancer Res 2007, 27:889-894.
25. Kluger H.M., Siddiqui S.F., Angeletti C., Sznol M., Kelly W.K., Molinaro A.M., et al. Classification of renal cell carcinoma based on expression of VEGF and VEGF receptors in both tumor cells and endothelial cells. Lab Invest 2008, 88:962-972.
26. Bierer S., Herrmann E., Kopke T., Neumann J., Eltze E., Hertle L., et al. Lymphangiogenesis in kidney cancer: expression of VEGF-C, VEGF-D and VEGFR-3 in clear cell and papillary renal cell carcinoma. Oncol Rep 2008, 20:721-725.
27. Voss M., Steidler A., Grobholz R., Weiss C., Alken P., Michel M.S., et al. The lymphatic system and its specific growth factor vascular endothelial growth factor C in kidney tissue and in renal cell carcinoma. BJU Int 2008.
28. Klatte T., Seligson D.B., LaRochelle J., Shuch B., Said J.W., Riggs S.B., et al. Molecular signatures of localized clear cell renal cell carcinoma to predict disease-free survival after nephrectomy. Cancer Epidemiol Biomarkers Prev 2009, 18:894-900.
29. Dorevic G., Matusan-Ilijas K., Babarovic E., Hadzisejdic I., Grahovac M., Grahovac B., et al. Hypoxia inducible factor-1alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma. J Exp Clin Cancer Res 2009, 28:40.
30. Wilhelm S.M., Carter C., Tang L., Wilkie D., McNabola A., Rong H., 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, 64:7099-7109.
31. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2009;28:1061-8.
32. Mendel D.B., Laird A.D., Xin X., Louie S.G., Christensen J.G., Li G., 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. Clin Cancer Res 2003, 9:327-337.
33. Sundberg C., Ljungstrom M., Lindmark G., Gerdin B., Rubin K. Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol 1993, 143:1377-1388.
34. Lindahl P., Johansson B.R., Leveen P., Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997, 277:242-245.
35. Gee M.S., Procopio W.N., Makonnen S., Feldman M.D., Yeilding N.M., Lee W.M. Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 2003, 162:183-193.
36. Benjamin L.E., Hemo I., Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998, 125:1591-1598.
37. Fabian M.A., Biggs W.H., Treiber D.K., Atteridge C.E., Azimioara M.D., Benedetti M.G., et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005, 23:329-336.
38. Rini B.I., Wilding G., Hudes G., Stadler W.M., Kim S., Tarazi J., et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009, 27:4462-4468.
39. Hu-Lowe D.D., Zou H.Y., Grazzini M.L., Hallin M.E., Wickman G.R., Amundson K., 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. Clin Cancer Res 2008, 14:7272-7283.
40. D'Angelo G., Struman I., Martial J., Weiner R.I. Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc Natl Acad Sci U S A 1995, 92:6374-6378.
41. D'Angelo G., Lee H., Weiner R.I. cAMP-dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation. J Cell Biochem 1997, 67:353-366.
42. Hood J.D., Bednarski M., Frausto R., Guccione S., Reisfeld R.A., Xiang R., et al. Tumor regression by targeted gene delivery to the neovasculature. Science 2002, 296:2404-2407.
43. Alavi A., Hood J.D., Frausto R., Stupack D.G., Cheresh D.A. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003, 301:94-96.
44. Alavi A.S., Acevedo L., Min W., Cheresh D.A. Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res 2007, 67:2766-2772.
45. Kumar R., Knick V.B., Rudolph S.K., Johnson J.H., Crosby R.M., Crouthamel M.C., et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007, 6:2012-2021.
46. Motzer R.J., Escudier B., Oudard S., Hutson T.E., Porta C., Bracarda S., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008, 372:449-456.
47. Hudes G., Carducci M., Tomczak P., Dutcher J., Figlin R., Kapoor A., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356:2271-2281.
48. Humar R., Kiefer F.N., Berns H., Resink T.J., Battegay E.J. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002, 16:771-780.
49. Land S.C., Tee A.R. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem 2007, 282:20534-20543.
50. Pore N., Jiang Z., Shu H.K., Bernhard E., Kao G.D., Maity A. Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res 2006, 4:471-479.
51. Hamada K., Sasaki T., Koni P.A., Natsui M., Kishimoto H., Sasaki J., et al. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev 2005, 19:2054-2065.
52. Riesterer O., Zingg D., Hummerjohann J., Bodis S., Pruschy M. Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells. Oncogene 2004, 23:4624-4635.
53. Escudier B., Eisen T., Stadler W.M., Szczylik C., Oudard S., Siebels M., et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134.
54. Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., Rixe O., et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115-124.
55. Tsuchiya N., Sato K., Akao T., Kakinuma H., Sasaki R., Shimoda N., et al. Quantitative analysis of gene expressions of vascular endothelial growth factor-related factors and their receptors in renal cell carcinoma. Tohoku J Exp Med 2001, 195:101-113.
56. Rivet J., Mourah S., Murata H., Mounier N., Pisonero H., Mongiat-Artus P., et al. VEGF and VEGFR-1 are coexpressed by epithelial and stromal cells of renal cell carcinoma. Cancer 2008, 112:433-442.
57. Houk B.E., Bello C.L., Poland B., Rosen L.S., Demetri G.D., Motzer R.J. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 2009.
58. Rini B.I., Jaeger E., Weinberg V., Sein N., Chew K., Fong K., et al. Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int 2006, 98:756-762.
59. Choueiri T.K., Vaziri S.A., Jaeger E., Elson P., Wood L., Bhalla I.P., et al. von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol 2008, 180:860-865. discussion 5-6.
60. Fernando N.T., Koch M., Rothrock C., Gollogly L.K., D'Amore P.A., Ryeom S., et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 2008, 14:1529-1539.
61. Ebos J.M., Lee C.R., Christensen J.G., Mutsaers A.J., Kerbel R.S. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 2007, 104:17069-17074.
62. Guerrin M., Scotet E., Malecaze F., Houssaint E., Plouet J. Overexpression of vascular endothelial growth factor induces cell transformation in cooperation with fibroblast growth factor 2. Oncogene 1997, 14:463-471.
63. von Schwarzenberg K., Held S.A., Schaub A., Brauer K.M., Bringmann A., Brossart P. Proteasome inhibition overcomes the resistance of renal cell carcinoma cells against the PPARgamma ligand troglitazone. Cell Mol Life Sci 2009, 66:1295-1308.
64. Loewith R., Jacinto E., Wullschleger S., Lorberg A., Crespo J.L., Bonenfant D., et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002, 10:457-468.
65. Jacinto E., Loewith R., Schmidt A., Lin S., Ruegg M.A., Hall A., et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004, 6:1122-1128.
66. Inoki K., Guan K.L. Complexity of the TOR signaling network. Trends Cell Biol 2006, 16:206-212.
67. Liu L., Li F., Cardelli J.A., Martin K.A., Blenis J., Huang S. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 2006, 25:7029-7040.
68. O'Reilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006, 66:1500-1508.
69. Deprimo S.E., Bello C.L., Smeraglia J., Baum C.M., Spinella D., Rini B.I., 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.
70. Sosman JA, Flaherty KT, Atkins MB, McDermott DF, Rothenberg ML, Vermeulen WL, et al. Updated results of phase I trial of sorafenib and bevacizumab in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26.
71. Ratain M.J., Eisen T., Stadler W.M., Flaherty K.T., Kaye S.B., Rosner G.L., et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006, 24:2505-2512.
72. Escudier B., Eisen T., Stadler W.M., Szczylik C., Oudard S., Staehler M., et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009, 27:3312-3318.
73. Azad N.S., Posadas E.M., Kwitkowski V.E., Steinberg S.M., Jain L., Annunziata C.M., et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 2008, 26:3709-3714.
74. Feldman D.R., Baum M.S., Ginsberg M.S., Hassoun H., Flombaum C.D., Velasco S., et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009, 27:1432-1439.
75. Rini B.I., Garcia J.A., Cooney M.M., Elson P., Tyler A., Beatty K., et al. A phase I study of sunitinib plus bevacizumab in advanced solid tumors. Clin Cancer Res 2009, 15:6277-6283.
76. Patel P.H., Senico P.L., Curiel R.E., Motzer R.J. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2009, 7:24-27.
77. Patnaik A, Ricart A, Cooper J, Papadopoulos K, Beeram M, Mita C, et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib, a multi-targeted kinase inhibitor in combination with temsirolimus, and mTOR inhibitor in patients with advanced solid malignancies. J Clin Oncol 2007;25.
78. Merchan JR, Liu G, Fitch T, Picus J, Qin R, Pitot HC, et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: phase I safety and activity results. J Clin Oncol 2007;25.
79. Merchan JR, Pitot HC, Qin R, Liu G, Fitch TR, Picus J, et al. Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): safety and activity in RTKI refractory RCC patients. J Clin Oncol 2009;27.
80. Fong G.H., Rossant J., Gertsenstein M., Breitman M.L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995, 376:66-70.
81. Inai T., Mancuso M., Hashizume H., Baffert F., Haskell A., Baluk P., et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004, 165:35-52.
82. Polverino A., Coxon A., Starnes C., Diaz Z., DeMelfi T., Wang L., 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, 66:8715-8721.
83. Rugo H.S., Herbst R.S., Liu G., Park J.W., Kies M.S., Steinfeldt H.M., et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005, 23:5474-5483.
84. Rosen L.S., Kurzrock R., Mulay M., Van Vugt A., Purdom M., Ng C., et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007, 25:2369-2376.
85. Shibuya M., Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 2006, 312:549-560.
86. Karpanen T., Egeblad M., Karkkainen M.J., Kubo H., Yla-Herttuala S., Jaattela M., et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001, 61:1786-1790.
87. Rixe O., Bukowski R.M., Michaelson M.D., Wilding G., Hudes G.R., Bolte O., et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007, 8:975-984.
88. Holash J., Davis S., Papadopoulos N., Croll S.D., Ho L., Russell M., et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002, 99:11393-11398.
89. Rudge J.S., Holash J., Hylton D., Russell M., Jiang S., Leidich R., et al. Inaugural Article: VEGF trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A 2007, 104:18363-18370.
90. Gordan J.D., Bertout J.A., Hu C.J., Diehl J.A., Simon M.C. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 2007, 11:335-347.
91. Bertout J.A., Majmundar A.J., Gordan J.D., Lam J.C., Ditsworth D., Keith B., et al. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci U S A 2009, 106:14391-14396.
92. Park E.J., Kong D., Fisher R., Cardellina J., Shoemaker R.H., Melillo G. Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle 2006, 5:1847-1853.
93. Majumder P.K., Febbo P.G., Bikoff R., Berger R., Xue Q., McMahon L.M., et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004, 10:594-601.
94. Flugel D., Gorlach A., Michiels C., Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007, 27:3253-3265.
95. Jung J.E., Lee H.G., Cho I.H., Chung D.H., Yoon S.H., Yang Y.M., et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J 2005, 19:1296-1298.
96. Qian D.Z., Kachhap S.K., Collis S.J., Verheul H.M., Carducci M.A., Atadja P., et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 2006, 66:8814-8821.
97. Litz J., Krystal G.W. Imatinib inhibits c-Kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. Mol Cancer Ther 2006, 5:1415-1422.
98. Isaacs J.S., Jung Y.J., Mole D.R., Lee S., Torres-Cabala C., Chung Y.L., et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005, 8:143-153.
99. Lin P., Buxton J.A., Acheson A., Radziejewski C., Maisonpierre P.C., Yancopoulos G.D., et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc Natl Acad Sci U S A 1998, 95:8829-8834.
100. Jouanneau J., Plouet J., Moens G., Thiery J.P. FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. Oncogene 1997, 14:671-676.
101. Kuba K., Matsumoto K., Date K., Shimura H., Tanaka M., Nakamura T. HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 2000, 60:6737-6743.
102. Hainsworth J.D., Sosman J.A., Spigel D.R., Edwards D.L., Baughman C., Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005, 23:7889-7896.
103. Motzer RJ, Hudes GR, Ginsberg MS, Baum MS, Harmon CS, Kim ST, et al. Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma. Am J Clin Oncol. 2010 Feb 5. [Epub ahead of print].
104. Rowinsky E.K., Schwartz G.H., Gollob J.A., Thompson J.A., Vogelzang N.J., Figlin R., et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004, 22:3003-3015.
105. Dawson N.A., Guo C., Zak R., Dorsey B., Smoot J., Wong J., et al. A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res 2004, 10:7812-7819.
106. Ayers M., Fargnoli J., Lewin A., Wu Q., Platero J.S. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res 2007, 67:6899-6906.
107. Zou H.Y., Li Q., Lee J.H., Arango M.E., McDonnell S.R., Yamazaki S., et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007, 67:4408-4417.
108. Lubensky I.A., Schmidt L., Zhuang Z., Weirich G., Pack S., Zambrano N., et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 1999, 155:517-526.
109. Qian F., Engst S., Yamaguchi K., Yu P., Won K.A., Mock L., et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69:8009-8016.
110. Mekhail T, Rich T, Rosen L, Chai F, Semic-Suka Z, Savage RE, et al. Final results: a dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors. J Clin Oncol 2009;27:3548.
111. Baba M., Hong S.B., Sharma N., Warren M.B., Nickerson M.L., Iwamatsu A., et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006, 103:15552-15557.