Targeted treatments in colorectal cancer: state of the art and future perspectives

Targeted treatments have generated a lot of hope and hype in the treatment of gastrointestinal tumours. Indeed, the introduction of targeted treatments particularly for colorectal cancer has resulted in substantial improvements in tumour response and progression-free survival of patients. However, it is not fully understood how these agents act in patients, and the preclinical models are not appropriate to predict clinical efficacy. Here the current state of targeted treatments in colorectal cancer is reviewed, focusing on antiepidermal growth factor receptor (EGFR) and antiangiogenic strategies, describing how these agents fit into the therapeutic algorithm of this disease and discussing current understanding of the mechanism of action, biomarkers as well as future therapeutic strategies targeting multiple signalling pathways in colorectal cancer.

[1]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[2]  S. Fan,et al.  Clinical implications of circulating angiogenic factors in cancer patients. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  S. Parsons,et al.  Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Katayama,et al.  Mitotic kinase expression and colorectal cancer progression. , 1999, Journal of the National Cancer Institute.

[5]  P. Loehrer Both Antiangiogenesis- and Angiogenesis-Independent Effects Are Responsible for Hepatocellular Carcinoma Growth Arrest by Tyrosine kinase Inhibitor PTK787/ZK222584 , 2006 .

[6]  Richard L Schilsky,et al.  Cetuximab in the treatment of colorectal cancer. , 2004, Clinical advances in hematology & oncology : H&O.

[7]  Violeta Serra,et al.  Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. , 2008, Cancer research.

[8]  D. Lambrechts,et al.  PIK3CA Mutations Are Not a Major Determinant of Resistance to the Epidermal Growth Factor Receptor Inhibitor Cetuximab in Metastatic Colorectal Cancer , 2009, Clinical Cancer Research.

[9]  R. Motzer,et al.  Targeted therapy for metastatic renal cell carcinoma , 2006, British Journal of Cancer.

[10]  R. Knuechel,et al.  Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[12]  S. Curley,et al.  Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. , 1993, The Journal of clinical investigation.

[13]  L. Mazzucchelli,et al.  Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  W. Scheithauer,et al.  EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  E. Van Cutsem,et al.  Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study , 2008, Clinical Cancer Research.

[17]  E. Rock,et al.  Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[18]  Robert Jones,et al.  A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake , 2005, Clinical Cancer Research.

[19]  S. Hankinson,et al.  Insulin-like growth factors and neoplasia , 2004, Nature Reviews Cancer.

[20]  I. Floriani,et al.  High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. , 2008, The oncologist.

[21]  Till Acker,et al.  Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions , 2001, Nature Medicine.

[22]  Manuel Hidalgo,et al.  An Epidermal Growth Factor Receptor Intron 1 Polymorphism Mediates Response to Epidermal Growth Factor Receptor Inhibitors , 2004, Cancer Research.

[23]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[24]  C. Stroh,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) , 2008 .

[25]  C. Köhne,et al.  Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[27]  H. Hurwitz,et al.  Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. Caruso,et al.  EGFR-targeted therapy in colorectal cancer: does immunohistochemistry deserve a role in predicting the response to cetuximab? , 2008, Current opinion in molecular therapeutics.

[29]  Sanjay Goel,et al.  PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. , 2008, Cancer research.

[30]  J. Baselga,et al.  NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. , 2008, Cancer research.

[31]  J. Baselga,et al.  The Epidermal Growth Factor Receptor Pathway: A Model for Targeted Therapy , 2006, Clinical Cancer Research.

[32]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[33]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[34]  E. Van Cutsem,et al.  KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  Stephen S. Taylor,et al.  Aurora-kinase inhibitors as anticancer agents , 2004, Nature Reviews Cancer.

[36]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[37]  G. Martiny-Baron,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. , 2000, Cancer research.

[38]  H. Lenz,et al.  Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  G. Jayson,et al.  Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP , 2006, British Journal of Cancer.

[40]  Ricky T. Tong,et al.  Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  J. Witte,et al.  Monoclonal antibody therapy for resected Dukes' C colorectal cancer: seven-year outcome of a multicenter randomized trial. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  F. Lordick,et al.  Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[43]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[44]  L. Ellis,et al.  VEGF-targeted therapy: mechanisms of anti-tumour activity , 2008, Nature Reviews Cancer.

[45]  Christoph Dehio,et al.  Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1 , 2003, Nature Medicine.

[46]  F. Caponigro,et al.  The proteasome: a worthwhile target for the treatment of solid tumours? , 2007, European journal of cancer.

[47]  Violeta Serra,et al.  NVP-BEZ 235 , a Dual PI 3 K / mTOR Inhibitor , Prevents PI 3 K Signaling and Inhibits the Growth of Cancer Cells with Activating PI 3 K Mutations , 2008 .

[48]  A. Jubb,et al.  Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. , 2005, Journal of the National Cancer Institute.

[49]  G. Riethmüller,et al.  Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma , 1994, The Lancet.

[50]  J. Mestan,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. , 2000, Cancer research.

[51]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[52]  Emad S. Alnemri,et al.  correction: A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis , 2001, Nature.

[53]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  G. Gallick,et al.  Src family kinases in tumor progression and metastasis , 2003, Cancer and Metastasis Reviews.

[55]  W. Scheithauer,et al.  Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.

[57]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[58]  Quynh-Thu Le,et al.  Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. , 2008, The New England journal of medicine.

[59]  Gregory Karczmar,et al.  Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  R. Berardi,et al.  Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  J. Weitz,et al.  Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. , 2010, The Lancet. Oncology.

[62]  Seta Shahin,et al.  A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[64]  J. Forster,et al.  Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Mathew J Garnett,et al.  Guilty as charged: B-RAF is a human oncogene. , 2004, Cancer cell.

[66]  C. Porta,et al.  Targeting Cancer Stem Cells to Modulate Alternative Vascularization Mechanisms , 2008, Stem Cell Reviews.

[67]  A. Jubb,et al.  Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  S. Rafii,et al.  Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. , 2000, The Journal of clinical investigation.

[69]  Lee M Ellis,et al.  Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells , 2005, Oncogene.

[70]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[71]  L. Ellis,et al.  Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  N. Funel,et al.  PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  Francesca Molinari,et al.  PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. , 2009, Cancer research.

[74]  C. Bokemeyer,et al.  Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  Zhenbao Yu,et al.  Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. , 2003, Carcinogenesis.

[76]  J. Baselga,et al.  Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  F. Habib,et al.  The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion. , 2007, Human pathology.

[78]  Marc Peeters,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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[79]  E. Chiocca,et al.  Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[80]  S. Fan,et al.  Both antiangiogenesis- and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. , 2005, Cancer research.

[81]  G. Mills,et al.  A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. , 2008, Cancer research.

[82]  S. Misbah,et al.  Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. , 2008, The New England journal of medicine.

[83]  G. Baretton,et al.  Overexpression of the insulin‐like growth factor I receptor in human colon carcinomas , 2002, Cancer.

[84]  Barry Sloan,et al.  Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. , 2008, Current opinion in investigational drugs.

[85]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[86]  R. Fonseca,et al.  Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  Ricky T. Tong,et al.  Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer , 2004, Nature Medicine.

[88]  M. Giacca,et al.  Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels , 2007, Cell.

[89]  Daniel J. Freeman,et al.  Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. , 2008, Clinical colorectal cancer.

[90]  G. D'Haens,et al.  A phase II, double-blind, randomized multicenter study of cediranib with FOLFOX versus bevacizumab with FOLFOX in patients with previously treated metastatic colorectal cancer (mCRC): Final PFS results , 2008 .

[91]  T. Rohan,et al.  Role of the insulin-like growth factor family in cancer development and progression. , 2000, Journal of the National Cancer Institute.

[92]  F. Kabbinavar,et al.  Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[93]  Lee M Ellis,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. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[94]  M. Gonen,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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[96]  V. Heinemann,et al.  Cetuximab plus XELIRI or XELOX for first-line therapy of metastatic colorectal cancer. , 2008, Clinical colorectal cancer.

[97]  E. Van Cutsem,et al.  Results of an interim analysis of a multinational randomized, double-blind, phase III study in patients (pts) with previously treated metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo (CONFIRM 2). , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[98]  M. Frieden,et al.  The application of locked nucleic acids in the treatment of cancer. , 2006, IDrugs : the investigational drugs journal.

[99]  E. Van Cutsem,et al.  Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  R. Abraham,et al.  The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy , 2007, Clinical Cancer Research.

[101]  A. Kopp-Schneider,et al.  Adjuvant Therapy with Edrecolomab versus Observation in Stage II Colon Cancer: A Multicenter Randomized Phase III Study* , 2005, Oncology Research and Treatment.

[102]  S. Paggi,et al.  Sorafenib in Advanced Hepatocellular Carcinoma , 2008 .

[103]  Emad S. Alnemri,et al.  A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis , 2001, Nature.

[104]  L. Ellis,et al.  Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin‐based chemotherapy for colorectal liver metastases , 2007, Cancer.

[105]  Stephen S. Taylor,et al.  Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores , 2003, The Journal of cell biology.

[106]  Michael B. Yaffe,et al.  Cytokine-Induced Signaling Networks Prioritize Dynamic Range over Signal Strength , 2008, Cell.

[107]  P. Catalano,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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[108]  N. Gray,et al.  Rational design of inhibitors that bind to inactive kinase conformations , 2006, Nature chemical biology.

[109]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.

[110]  M. Aapro,et al.  Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  J. Hecht,et al.  Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  R. Seruca,et al.  BRAF provides proliferation and survival signals in MSI colorectal carcinoma cells displaying BRAFV600E but not KRAS mutations , 2008, The Journal of pathology.

[113]  P. Hahnfeldt,et al.  Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. , 2002, Journal of the National Cancer Institute.

[114]  G. Yancopoulos,et al.  VEGF-Trap: A VEGF blocker with potent antitumor effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[115]  H. Ludwig,et al.  The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer , 1993, Cancer.

[116]  S. Curley,et al.  Extended Preoperative Chemotherapy Does Not Improve Pathologic Response and Increases Postoperative Liver Insufficiency After Hepatic Resection for Colorectal Liver Metastases , 2010, Annals of Surgical Oncology.

[117]  N. Goldstein,et al.  Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[118]  T. Seufferlein,et al.  Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[119]  A. Adjei,et al.  Phase I Dose Escalation Study of the Anti–Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors , 2007, Clinical Cancer Research.

[120]  C. Amos,et al.  IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. , 2006, Journal of the National Cancer Institute.

[121]  G. Corner,et al.  DR 5 Receptor Mediates Anoikis in Human Colorectal Carcinoma Cell Lines , 2008 .

[122]  K. Hellmann,et al.  Recognition of tumor blood vessel normalization as a new antiangiogenic concept , 2004, Nature Medicine.

[123]  D. McDonald,et al.  Rapid vascular regrowth in tumors after reversal of VEGF inhibition. , 2006, The Journal of clinical investigation.

[124]  K. Kawakami,et al.  BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status , 2006, Molecular Cancer.

[125]  G. Corner,et al.  DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. , 2008, Cancer research.

[126]  A. Scott,et al.  Phase I Trial of 131 I-huA 33 in Patientswith Advanced Colorectal Carcinoma , 2005 .

[127]  C. Punt,et al.  Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study , 2002, The Lancet.

[128]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[129]  Daniel B Longley,et al.  c-FLIP: a key regulator of colorectal cancer cell death. , 2007, Cancer research.

[130]  E. D. de Vries,et al.  Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[131]  N. Quenville,et al.  Prognostic markers of colorectal cancer: An evaluation of DNA content, epidermal growth factor receptor, and Ki‐67 , 1992, Journal of surgical oncology.

[132]  M. Koopman,et al.  A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[133]  H. Mackay,et al.  A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer , 2005, Clinical Cancer Research.

[134]  D. Hwang,et al.  Gastrosplenic fistula from Hodgkin's lymphoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[135]  Leonard,et al.  Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. , 1997, Cancer research.

[136]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[137]  G. Yancopoulos,et al.  VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade , 2007, Proceedings of the National Academy of Sciences.

[138]  P. Jänne,et al.  Responsiveness to cetuximab without mutations in EGFR. , 2005, The New England journal of medicine.

[139]  J. Berlin,et al.  Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab , 2005, Journal of surgical oncology.

[140]  Silvia Benvenuti,et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. , 2005, The Lancet. Oncology.

[141]  G. Fuh,et al.  Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells , 2007, Nature Biotechnology.

[142]  L. Lipton,et al.  Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours , 2008, British Journal of Cancer.

[143]  M. Sekine,et al.  Vascular Endothelial Growth Factor Mediates Intracrine Survival in Human Breast Carcinoma Cells through Internally Expressed VEGFR1/FLT1 , 2007, PLoS medicine.

[144]  L. Ellis,et al.  Vascular endothelial growth factor receptor‐1 promotes migration and invasion in pancreatic carcinoma cell lines , 2005, Cancer.

[145]  Jianhua Huang,et al.  A Role for VEGF as a Negative Regulator of Pericyte Function and Vessel Maturation , 2008, Nature.

[146]  A. Sweet-Cordero,et al.  Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon , 2008, Nature Genetics.

[147]  E. Vries,et al.  Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. , 2004 .

[148]  N. Ferrara,et al.  VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism , 2002, Nature.

[149]  L. Ellis,et al.  Tumors Established with Cell Lines Selected for Oxaliplatin Resistance Respond to Oxaliplatin if Combined with Cetuximab , 2007, Clinical Cancer Research.

[150]  E. Van Cutsem,et al.  Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab , 2007, British Journal of Cancer.

[151]  H. Hurwitz,et al.  The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. , 2009, The oncologist.

[152]  E. Van Cutsem,et al.  Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): Outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[153]  D. Lawrence,et al.  Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5 , 2008, Cell Death and Differentiation.

[154]  Na Zhang,et al.  Deletion of Vascular Endothelial Growth Factor in myeloid cells accelerates tumorigenesis , 2008, Nature.

[155]  John M L Ebos,et al.  Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. , 2009, Cancer cell.

[156]  R. Berardi,et al.  Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options , 2007, British Journal of Cancer.

[157]  Martin R. Schneider,et al.  PTK 787 / 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 , 2000 .

[158]  Eugene S. Kim,et al.  Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. , 2004, Molecular cancer research : MCR.

[159]  Kenneth J. Hillan,et al.  Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer , 2004, Nature Reviews Drug Discovery.

[160]  A. Grothey,et al.  Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial , 2008 .

[161]  Lloyd J. Old,et al.  Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma , 2005, Clinical Cancer Research.