Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling Pathways as Therapeutic Targets for Colorectal Cancer

Gastroenterology

Volumn 138, Issue 6, 2010, Pages 2163-2176

  Winder, Thomas ^a   Lenz, Heinz Josef ^a,b  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

EGFR Pathway; Targeted Treatment; VEGF Pathway

Indexed keywords

AFLIBERCEPT; BEVACIZUMAB; CAPECITABINE; CETUXIMAB; EPIDERMAL GROWTH FACTOR; ERLOTINIB; FLUOROPYRIMIDINE; FLUOROURACIL; FOLINIC ACID; GEFITINIB; IRINOTECAN; OXALIPLATIN; PANITUMUMAB; PLACEBO; SUNITINIB; VASCULOTROPIN; VATALANIB;

ACNE; ARTICLE; BLOOD TOXICITY; CANCER INHIBITION; CANCER RESISTANCE; CLINICAL TRIAL; COLORECTAL CANCER; COLORECTAL TUMOR; DIARRHEA; DIGESTIVE SYSTEM PERFORATION; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG ERUPTION; DRUG FEVER; DRUG HYPERSENSITIVITY; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DRUG WITHDRAWAL; EPISTAXIS; GENE MUTATION; HUMAN; HYPERTENSION; HYPOMAGNESEMIA; LIVER METASTASIS; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; MACULOPAPULAR RASH; NAIL DISEASE; NEUROPATHY; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; OVARY CANCER; OVERALL SURVIVAL; PANCREAS CANCER; PRIORITY JOURNAL; PROGNOSIS; PROGRESSION FREE SURVIVAL; PROSTATE CANCER; PROTEINURIA; SIGNAL TRANSDUCTION; SKIN TOXICITY; SURVIVAL TIME; THROMBOSIS; TUMOR VASCULARIZATION; WOUND HEALING IMPAIRMENT;

EID: 77951643701     PISSN: 00165085     EISSN: None     Source Type: Journal    
DOI: 10.1053/j.gastro.2010.02.005     Document Type: Article

References (97)

1. Mendelsohn J., and Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21 (2003) 2787-2799
2. Yarden Y., and Sliwkowski M.X. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2 (2001) 127-137
3. Liu D., Aguirre Ghiso J., Estrada Y., et al. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1 (2002) 445-457
4. Lewis T.S., Shapiro P.S., and Ahn N.G. Signal transduction through MAP kinase cascades. Adv Cancer Res 74 (1998) 49-139
5. Di Cristofano A., and Pandolfi P.P. The multiple roles of PTEN in tumor suppression. Cell 100 (2000) 387-390
6. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10 (1998) 262-267
7. Capdevila J., Elez E., Macarulla T., et al. Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev 35 (2009) 354-363
8. Kawamoto T., Sato J.D., Le A., et al. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A 80 (1983) 1337-1341
9. Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res 5 (2007) 203-220
10. Prewett M.C., Hooper A.T., Bassi R., et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8 (2002) 994-1003
11. Lenz H.J., Van Cutsem E., Khambata-Ford S., et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24 (2006) 4914-4921
12. Saltz L.B., Meropol N.J., Loehrer P.J., et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22 (2004) 1201-1208
13. Cunningham D., Humblet Y., Siena S., et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 (2004) 337-345
14. Saltz L.B., Kies M., Abbruzzese J.L., et al. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies (abstr 817). Proc Am Soc Clin Oncol 22 (2003) 204
15. Tejpar S., Peeters M., Humblet Y., et al. Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): the EVEREST experience (preliminary data). (abstr 4001). J Clin Oncol 26 May 20 Suppl (2008)
16. Van Cutsem E., Nowacki M., Lang I., et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. (abstr 4000). J Clin Oncol 25 Suppl (2007)
17. Bokemeyer C., Bondarenko I., Makhson A., et al. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study. (abstr 4035). J Clin Oncol 25 Suppl (2007)
18. Lievre A., Bachet J.B., Le Corre D., et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66 (2006) 3992-3995
19. Kohne C., Stroiakovski D., Chang-Chien C., et al. Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial (abstr 4068). J Clin Oncol 27 Suppl (2009)
20. Van Cutsem E., Rougier P., Köhne C., et al. A meta-analysis of the CRYSTAL and OPUS studies combining cetuximab with chemotherapy (CT) as 1st-line treatment for patients (pts) with metastatic colorectal cancer (mCRC): results according to KRAS and BRAF mutation status. (abstr 6077). Eur J Cancer Suppl 7 (2009) 345
21. Bokemeyer C., Bondarenko I., Hartmann T.J., et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience (abstr 4000). J Clin Oncol 26 Suppl (2008)
22. Karapetis C.S., Khambata-Ford S., Jonker D.J., et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359 (2008) 1757-1765
23. Di Nicolantonio F., Martini M., Molinari F., et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26 (2008) 5705-5712
24. Zhang W., Gordon M., Schultheis A.M., et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25 (2007) 3712-3718
25. Lurje G., Nagashima F., Zhang W., et al. Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res 14 (2008) 7884-7895
26. Sobrero A.F., Maurel J., Fehrenbacher L., et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26 (2008) 2311-2319
27. Gravalos C., Cassinello J., Garcia-Alfonso P., et al. Integration of panitumumab into the treatment of colorectal cancer. Crit Rev Oncol Hematol 74 (2010) 16-26
28. Weiner L.M., Belldegrun A.S., Crawford J., et al. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res 14 (2008) 502-508
29. Hecht J.R., Patnaik A., Berlin J., et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 110 (2007) 980-988
30. Van Cutsem E., Peeters M., Siena S., et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 (2007) 1658-1664
31. Berlin J., Posey J., Tchekmedyian S., et al. Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 6 (2007) 427-432
32. Douillard J., Siena S., Cassidy J., et al. Randomized phase 3 study of panitumumab with FOLFOX-4 compared to FOLFOX-4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial (abstr 10LBA). Eur J Cancer Suppl 7 3 (2009) 6
33. Peeters M, Wilson G, Hotko Y, et al. Phase III study (20050181) of panitumumab with FOLFIRI compared to FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer (mCRC): preliminary safety results (abstr 335). Abstract presented at: ASCO Gastrointestinal Cancers Symposium; Orlando, FL; January 25-27, 2008.
34. Amado R.G., Wolf M., Peeters M., et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26 (2008) 1626-1634
35. Albanell J., Rojo F., and Baselga J. Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839. Semin Oncol 28 (2001) 56-66
36. Baselga J., Rischin D., Ranson M., et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20 (2002) 4292-4302
37. Rothenberg M.L., LaFleur B., Levy D.E., et al. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 23 (2005) 9265-9274
38. Kuo T., Cho C.D., Halsey J., et al. Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol 23 (2005) 5613-5619
39. Fisher G.A., Kuo T., Ramsey M., et al. A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer. Clin Cancer Res 14 (2008) 7074-7079
40. Chau I., Cunningham D., Hickish T., et al. Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study. Ann Oncol 18 (2007) 730-737
41. Wolpin B.M., Clark J.W., Meyerhardt J.A., et al. Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer. Clin Colorectal Cancer 6 (2006) 208-213
42. Moyer J.D., Barbacci E.G., Iwata K.K., et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57 (1997) 4838-4848
43. Townsley C.A., Major P., Siu L.L., et al. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94 (2006) 1136-1143
44. Hanauske A.R., Cassidy J., Sastre J., et al. Phase 1b dose escalation study of erlotinib in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors. Clin Cancer Res 13 (2007) 523-531
45. Meyerhardt J.A., Stuart K., Fuchs C.S., et al. Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Ann Oncol 18 (2007) 1185-1189
46. Bajetta E., Di Bartolomeo M., Buzzoni R., et al. Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients. Cancer Chemother Pharmacol 64 (2009) 67-72
47. Wagner A.D., Arnold D., Grothey A.A., et al. Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Database Syst Rev (2009) CD005392
48. Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315 (1986) 1650-1659
49. Bergers G., and Benjamin L.E. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3 (2003) 401-410
50. McDonald D.M., and Baluk P. Significance of blood vessel leakiness in cancer. Cancer Res 62 (2002) 5381-5385
51. Folberg R., Hendrix M.J., and Maniotis A.J. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156 (2000) 361-381
52. Lyden D., Hattori K., Dias S., et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7 (2001) 1194-1201
53. Tischer E., Mitchell R., Hartman T., et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266 (1991) 11947-11954
54. Ferrara N., Gerber H.P., and LeCouter J. The biology of VEGF and its receptors. Nat Med 9 (2003) 669-676
55. Grothey A., and Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 6 (2009) 507-518
56. Grothey A., and Ellis L.M. Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J 14 (2008) 170-177
57. LeCouter J., Moritz D.R., Li B., et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299 (2003) 890-893
58. Hicklin D.J., and Ellis L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23 (2005) 1011-1027
59. Shibuya M. Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. BMB Rep 41 (2008) 278-286
60. Wherle C., Van Slyke P., and Dumont D.J. Angiopoietin-1 induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation. Biochem J 423 (2009) 375-380
61. Adams R.H., and Klein R. Eph receptors and ephrin ligands. Essential mediators of vascular development. Trends Cardiovasc Med 10 (2000) 183-188
62. Noguera-Troise I., Daly C., Papadopoulos N.J., et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444 (2006) 1032-1037
63. Mizukami Y., Jo W.S., Duerr E.M., et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11 (2005) 992-997
64. Lurje G., Zhang W., Schultheis A.M., et al. Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol 19 (2008) 1734-1741
65. Kim K.J., Li B., Winer J., et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362 (1993) 841-844
66. Warren R.S., Yuan H., Matli M.R., et al. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 95 (1995) 1789-1797
67. Gordon M.S., Margolin K., Talpaz M., et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19 (2001) 843-850
68. Kabbinavar F., Hurwitz H.I., Fehrenbacher L., et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21 (2003) 60-65
69. Hurwitz H., Fehrenbacher L., Novotny W., et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (2004) 2335-2342
70. Scappaticci F.A., Fehrenbacher L., Cartwright T., et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 91 (2005) 173-180
71. Saltz L.B., Clarke S., Diaz-Rubio E., et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26 (2008) 2013-2019
72. Hochster H.S., Hart L.L., Ramanathan R.K., et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26 (2008) 3523-3529
73. Grothey A., Sugrue M.M., Purdie D.M., et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26 (2008) 5326-5334
74. Allegra C.J., Yothers G., O'Connell M.J., et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol 27 (2009) 3385-3390
75. Wolmark N., Yothers G., O'Connell M.J., et al. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: results of NASABP Protocol C-08 (abstr LBA4). J Clin Oncol 27 Suppl (2009)
76. Giantonio B.J., Catalano P.J., Meropol N.J., et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25 (2007) 1539-1544
77. Drevs J., Hofmann I., Hugenschmidt H., et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res 60 (2000) 4819-4824
78. Thomas A.L., Trarbach T., Bartel C., et al. A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer. Ann Oncol 18 (2007) 782-788
79. Hecht J.R., Trarbach T., Jaeger E., et al. A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK222584 or placebo (CONFIRM-1). (abstr 3). J Clin Oncol 23 Suppl (2005)
80. Kohne C., Bajetta E., Lin E., et al. Final results of CONFIRM 2: a multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK222584 (PTK/ZK) or placebo (abstr 4033). J Clin Oncol 25 Suppl (2007)
81. Holash J., Davis S., Papadopoulos N., et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 99 (2002) 11393-11398
82. Tang P., Cohen S.J., Bjarnason G.A., et al. Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): a PMH phase II consortium trial. (abstr 4027). J Clin Oncol 26 Suppl (2008)
83. Starling N, Cunningham D, Vazquez F, et al. A phase I study of sunitinib in combination with FOLFIRI chemotherapy in treatment-naive, metastatic colorectal cancer. Poster presented at: ASCO Gastrointestinal Cancers Symposium; Orlando, FL; January 19-21, 2007.
84. Leong S, Eckhardt SG, Chan E, et al. A phase I study of sunitinib in combination with modified FOLFOX 6 (mFOLFOX6) chemotherapy (abstr 285). Presented at: ASCO Gastrointestinal Cancers Symposium; Orlando, FL; January 19-21, 2007.
85. Kim S.J., Uehara H., Karashima T., et al. Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clin Cancer Res 9 (2003) 1200-1210
86. Perrotte P., Matsumoto T., Inoue K., et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5 (1999) 257-265
87. Ellis L.M. Epidermal growth factor receptor in tumor angiogenesis. Hematol Oncol Clin North Am 18 (2004) 1007-1021 viii
88. Saltz L.B., Lenz H.J., Kindler H.L., et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 25 (2007) 4557-4561
89. Hecht JR, Mitchell EP, Chidiac T, et al. Interim results from PACCE: irinotecan (Iri)/vebacizumab (bev) +/- panitumumab (pmab) as first-line treatment (tx) for metastatic colorectal cancer (mCRC) (abstr 279). Presented at: ASCO Gastrointestinal Cancers Symposium; Orlando, FL; January 25-27, 2007.
90. Punt C.J., Tol J., Rodenburg C.J., et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). (abstr LBA4011). J Clin Oncol 26 Suppl (2008)
91. Ciardiello F., and Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 358 (2008) 1160-1174
92. Han S.W., Kim T.Y., Hwang P.G., et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23 (2005) 2493-2501
93. Riely G.J., Pao W., Pham D., et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12 (2006) 839-844
94. Barber T.D., Vogelstein B., Kinzler K.W., et al. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351 (2004) 2883
95. Ellis L.M. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol 33 (2006) S1-S7
96. Ellis L.M., and Hicklin D.J. Resistance to targeted therapies: refining anticancer therapy in the era of molecular oncology. Clin Cancer Res 15 (2009) 7471-7478
97. Scartozzi M., Galizia E., Chiorrini S., et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 20 (2009) 227-230