Therapeutic modulation of k-ras signaling in colorectal cancer

Drug Discovery Today

Volumn 15, Issue 13-14, 2010, Pages 502-516

  Krens, Lisanne L ^a   Baas, Jara M ^a   Gelderblom, Hans ^a   Guchelaar, Henk Jan ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

3 BENZYL 7 CYANO 2,3,4,5 TETRAHYDRO 1 (1H IMIDAZOL 4 YLMETHYL) 4 (2 THIENYLSULFONYL) 1H 1,4 BENZODIAZEPINE; BENDAMUSTINE; BORTEZOMIB; CETUXIMAB; CYCLOPHOSPHAMIDE; DEXAMETHASONE; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR; FLUINDOSTATIN; FLUOROURACIL; FOLINIC ACID; FULVESTRANT; GEMCITABINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IRINOTECAN; K RAS PROTEIN; L 778123; LONAFARNIB; MEVALONIC ACID; MEVINOLIN; OCTREOTIDE; PACLITAXEL; PANITUMUMAB; PRAVASTATIN; SIMVASTATIN; THALIDOMIDE; TIPIFARNIB; UNINDEXED DRUG; VINCRISTINE; ZOLEDRONIC ACID;

ACUTE GRANULOCYTIC LEUKEMIA; ASTROCYTOMA; BRAIN STEM TUMOR; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CARCINOGENESIS; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; COLORECTAL CANCER; DRUG TARGETING; GLIOBLASTOMA; GLIOMA; HEAD AND NECK CARCINOMA; HUMAN; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; MULTIPLE MYELOMA; MUTANT; MYELODYSPLASTIC SYNDROME; ONCOGENE K RAS; PANCREAS CANCER; PHENOTYPE; PRENYLATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; STOMACH ADENOCARCINOMA; TREATMENT RESPONSE; UROGENITAL TRACT CANCER; UTERINE CERVIX CARCINOMA;

ANIMALS; ANTINEOPLASTIC AGENTS; COLORECTAL NEOPLASMS; ENZYME INHIBITORS; HUMANS; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 77954255389     PISSN: 13596446     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drudis.2010.05.012     Document Type: Review

References (154)

1. Jemal A., et al. Cancer statistics, 2009. CA Cancer J. Clin. 2009, 59:225-249.
2. Shimizu K., et al. Three human transforming genes are related to the viral ras oncogenes. Proc. Natl. Acad. Sci. U. S. A. 1983, 80:2112-2116.
3. Rowell C.A., et al. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J. Biol. Chem. 1997, 272:14093-14097.
4. Whyte D.B., et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 1997, 272:14459-14464.
5. Konstantinopoulos P.A., et al. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat. Rev. Drug Discov. 2007, 6:541-555.
6. Vogelstein B., et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 1988, 319:525-532.
7. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 2003, 3:11-22.
8. Graaf M.R., et al. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat. Rev. 2004, 30:609-641.
9. Buday L., Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 1993, 73:611-620.
10. Roberts P.J., Der C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007, 26:3291-3310.
11. Fang J.Y., Richardson B.C. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005, 6:322-327.
12. Heinemann V., et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat. Rev. 2009, 35:262-271.
13. Bos J.L., et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 1987, 327:293-297.
14. Forrester K., et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 1987, 327:298-303.
15. Artale S., et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J. Clin. Oncol. 2008, 26:4217-4219.
16. Brink M., et al. K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. Carcinogenesis 2003, 24:703-710.
17. Wojcik P., et al. KRAS mutation profile in colorectal carcinoma and novel mutation-internal tandem duplication in KRAS. Pol. J. Pathol. 2008, 59:93-96.
18. Kraus M.C., et al. The balanced induction of K-ras codon 12 and 13 mutations in mucosa differs from their ratio in neoplastic tissues. Int. J. Oncol. 2006, 29:957-964.
19. Andreyev H.J., et al. Kirsten ras mutations in patients with colorectal cancer: the multicenter " RASCAL" study. J. Natl. Cancer Inst. 1998, 90:675-684.
20. Sanchez-de-Abajo A., et al. Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. Clin. Cancer Res. 2007, 13:5729-5735.
21. Adjei A.A. Blocking oncogenic Ras signaling for cancer therapy. J. Natl. Cancer Inst. 2001, 93:1062-1074.
22. Tong L.A., et al. Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J. Mol. Biol. 1991, 217:503-516.
23. Scheffzek K., et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997, 277:333-338.
24. Khambata-Ford S., et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 2007, 25:3230-3237.
25. Anwar S., et al. Systematic review of genetic influences on the prognosis of colorectal cancer. Br. J. Surg. 2004, 91:1275-1291.
26. Graziano F., Cascinu S. Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough?. Ann. Oncol. 2003, 14:1026-1038.
27. Klump B., et al. Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature. Int. J. Colorectal Dis. 2004, 19:23-42.
28. Conlin A., et al. The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma. Gut 2005, 54:1283-1286.
29. Unknown author ASCO conference highlights: potential markers of response in NSCLC. Signal 2005, 6:12-16.
30. Russo A., et al. Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Ann. Oncol. 2005, 16(Suppl. 4):iv44-iv49.
31. Castagnola P., Giaretti W. Mutant KRAS, chromosomal instability and prognosis in colorectal cancer. Biochim. Biophys. Acta 2005, 1756:115-125.
32. Andreyev H.J., et al. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br. J. Cancer 2001, 85:692-696.
33. Amado R.G., et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008, 26:1626-1634.
34. Karapetis C.S., et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359:1757-1765.
35. Plesec T.P., Hunt J.L. KRAS mutation testing in colorectal cancer. Adv. Anat. Pathol. 2009, 16:196-203.
36. Tol J. et al. (2009) High sensitivity of both sequencing and real-time PCR analysis of KRAS mutations in colorectal cancer tissue. J. Cell Mol. Med. [Epub ahead of print].
37. van Krieken J.H., et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 2008, 453:417-431.
38. Juan T., et al. A comparability study of 4 commercial KRAS tests. AACR Meeting Abstracts 2008 2008, 1811.
39. Markowitz S.D., Bertagnolli M.M. Molecular origins of cancer: molecular basis of colorectal cancer. N. Engl. J. Med. 2009, 361:2449-2460.
40. Walther A., et al. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer 2009, 9:489-499.
41. Friday B.B., Adjei A.A. K-ras as a target for cancer therapy. Biochim. Biophys. Acta 2005, 1756:127-144.
42. Demierre M.F., et al. Statins and cancer prevention. Nat. Rev. Cancer 2005, 5:930-942.
43. Hentosh P., et al. Sterol-independent regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in tumor cells. Mol. Carcinog. 2001, 32:154-166.
44. Sassano A., Platanias L.C. Statins in tumor suppression. Cancer Lett. 2008, 260:11-19.
45. Jakobisiak M., et al. Cell cycle-specific effects of lovastatin. Proc. Natl. Acad. Sci. U. S. A. 1991, 88:3628-3632.
46. Siddiqui A.A., et al. For patients with colorectal cancer, the long-term use of statins is associated with better clinical outcomes. Dig. Dis. Sci. 2009, 54:1307-1311.
47. Sondergaard T.E., et al. A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma. Hematol. Oncol. 2009, 27:17-22.
48. van der Spek S.E., et al. High dose simvastatin does not reverse resistance to vincristine, adriamycin, and dexamethasone (VAD) in myeloma. Haematologica 2007, 92:e130-e131.
49. Schmidmaier R., et al. First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. Eur. J. Haematol. 2007, 79:240-243.
50. Graf H., et al. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion 2008, 78:34-38.
51. Lee J., et al. Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal patients: a multicenter phase II study. Cancer Chemother. Pharmacol. 2009, 64:657-663.
52. Crul M., et al. Ras biochemistry and farnesyl transferase inhibitors: a literature survey. Anticancer Drugs 2001, 12:163-184.
53. Sparano J.A., et al. Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin. Cancer Res. 2009, 15:2942-2948.
54. Lancet J.E., et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007, 109:1387-1394.
55. Basso A.D., et al. Lipid posttranslational modifications. Farnesyl transferase inhibitors. J. Lipid Res. 2006, 47:15-31.
56. Sebti S.M., Hamilton A.D. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 2000, 19:6584-6593.
57. Cox A.D. Farnesyltransferase inhibitors: potential role in the treatment of cancer. Drugs 2001, 61:723-732.
58. Harousseau J.L., et al. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood 2009, 114:1166-1173.
59. Brunner T.B., et al. Farnesyltransferase inhibitors as radiation sensitizers. Int. J. Radiat. Biol. 2003, 79:569-576.
60. Cengel K.A., et al. Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells. Neoplasia 2007, 9:341-348.
61. Brunner T.B., et al. Radiation sensitization by inhibition of activated Ras. Strahlenther. Onkol. 2004, 180:731-740.
62. Martin N.E., et al. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin. Cancer Res. 2004, 10:5447-5454.
63. Hahn S.M., et al. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin. Cancer Res. 2002, 8:1065-1072.
64. Walker K., Olson M.F. Targeting Ras and Rho GTPases as opportunities for cancer therapeutics. Curr. Opin. Genet. Dev. 2005, 15:62-68.
65. Sun J., et al. The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. J. Biol. Chem. 1999, 274:6930-6934.
66. Sun J., et al. Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res. 2003, 63:8922-8929.
67. Vogt A., et al. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J. Biol. Chem. 1997, 272:27224-27229.
68. Woodward J.K., et al. Preclinical evidence for the effect of bisphosphonates and cytotoxic drugs on tumor cell invasion. Anticancer Drugs 2005, 16:11-19.
69. Diel I.J. Bisphosphonates in the prevention of bone metastases: current evidence. Semin. Oncol. 2001, 28:75-80.
70. Aapro M., et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann. Oncol. 2008, 19:420-432.
71. Gralow J., Tripathy D. Managing metastatic bone pain: the role of bisphosphonates. J. Pain Symptom Manage. 2007, 33:462-472.
72. Gnant M., et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 2009, 360:679-691.
73. Wang H., et al. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J. Biol. Chem. 1997, 272:25380-25385.
74. Winter-Vann A.M., et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc. Natl. Acad. Sci. U. S. A. 2003, 100:6529-6534.
75. Winter-Vann A.M., Casey P.J. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat. Rev. Cancer 2005, 5:405-412.
76. Ciardiello F., Tortora G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 2008, 358:1160-1174.
77. Li S., et al. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 2005, 7:301-311.
78. Imai K., Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat. Rev. Cancer 2006, 6:714-727.
79. Benvenuti S., et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007, 67:2643-2648.
80. Bibeau F., et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J. Clin. Oncol. 2009, 27:1122-1129.
81. Bokemeyer C., et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 2009, 27:663-671.
82. De Roock W., et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol. 2008, 19:508-515.
83. Di Nicolantonio F., et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol. 2008, 26:5705-5712.
84. Garm Spindler K.L., et al. The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer. Ann. Oncol. 2009, 20:879-884.
85. Lievre A., et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66:3992-3995.
86. Lievre A., et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008, 26:374-379.
87. Prenen H., et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res. 2009, 15:3184-3188.
88. Tol J., et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N. Engl. J. Med. 2009, 360:563-572.
89. Allegra C.J., et al. American Society of Clinical Oncology Provisional Clinical Opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 2009, 27:2091-2096.
90. Linardou H., et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008, 9:962-972.
91. Douillard J., et al. Phase III study (PRIME/20050203) of panitumumab with FOLFOX4 compared to FOLFOX4 alone in patients with previously untreated metastatic colorectal cancer (mCRC): preliminary safety data. ASCO Meeting Abstracts 2009.
92. Mantha A.J., et al. Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin. Cancer Res. 2005, 11:2398-2407.
93. Bos J.L. ras oncogenes in human cancer: a review. Cancer Res. 1989, 49:4682-4689.
94. Lopez-Aguilar E., et al. Phase II study of metronomic chemotherapy with thalidomide, carboplatin-vincristine-fluvastatin in the treatment of brain stem tumors in children. Arch. Med. Res. 2008, 39:655-662.
95. Knox J.J., et al. A phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur. J. Cancer 2005, 41:523-530.
96. Lersch C., et al. Treatment of HCC with pravastatin, octreotide, or gemcitabine - a critical evaluation. Hepatogastroenterology 2004, 51:1099-1103.
97. Kim W.S., et al. Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest. New Drugs 2001, 19:81-83.
98. Kawata S., et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br. J. Cancer 2001, 84:886-891.
99. Larner J., et al. A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am. J. Clin. Oncol. 1998, 21:579-583.
100. Thibault A., et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin. Cancer Res. 1996, 2:483-491.
101. Li T., et al. Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205. Ann. Oncol. 2009, 20:642-647.
102. Lustig R., et al. Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease. Neuro-oncology 2008, 10:1004-1009.
103. Eckhardt S.G., et al. Patient-reported outcomes as a component of the primary endpoint in a double-blind, placebo-controlled trial in advanced pancreatic cancer. J. Pain Symptom Manage. 2009, 37:135-143.
104. Ravoet C., et al. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study. Ann. Hematol. 2008, 87:881-885.
105. Feldman E.J., et al. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia 2008, 22:1707-1711.
106. Karp J.E., et al. Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin. Cancer Res. 2008, 14:3077-3082.
107. Fouladi M., et al. A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study. Cancer 2007, 110:2535-2541.
108. Johnston S.R., et al. Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J. Clin. Oncol. 2003, 21:2492-2499.
109. Harousseau J.L., et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia. Blood 2007, 109:5151-5156.
110. Cloughesy T.F., et al. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J. Clin. Oncol. 2006, 24:3651-3656.
111. Whitehead R.P., et al. Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study. Invest. New Drugs 2006, 24:335-341.
112. Borthakur G., et al. Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy. Cancer 2006, 106:346-352.
113. Macdonald J.S., et al. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest. New Drugs 2005, 23:485-487.
114. Kim E.S., et al. Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma. Cancer 2005, 104:561-569.
115. Theodore C., et al. Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur. J. Cancer 2005, 41:1150-1157.
116. Winquist E., et al. A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer. Urol. Oncol. 2005, 23:143-149.
117. Rosenberg J.E., et al. A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma. Cancer 2005, 103:2035-2041.
118. Rao S., et al. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J. Clin. Oncol. 2004, 22:3950-3957.
119. Heymach J.V., et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer. Ann. Oncol. 2004, 15:1187-1193.
120. Van Cutsem E., et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 2004, 22:1430-1438.
121. Kurzrock R., et al. Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J. Clin. Oncol. 2004, 22:1287-1292.
122. Alsina M., et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004, 103:3271-3277.
123. Adjei A.A., et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 2003, 21:1760-1766.
124. Cohen S.J., et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J. Clin. Oncol. 2003, 21:1301-1306.
125. Cortes J., et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003, 101:1692-1697.
126. Sharma S., et al. A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan. Ann. Oncol. 2002, 13:1067-1071.
127. James N.D., et al. Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial. BJU Int. 2009, 103:464-469.
128. Diel I.J., et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann. Oncol. 2008, 19:2007-2011.
129. Kristensen B., et al. Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncol. 2008, 47:740-746.
130. Kattan J.G., et al. Weekly docetaxel, zoledronic acid and estramustine in hormone-refractory prostate cancer (HRPC). Invest. New Drugs 2008, 26:75-79.
131. Mason M.D., et al. Oral sodium clodronate for nonmetastatic prostate cancer - results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J. Natl. Cancer Inst. 2007, 99:765-776.
132. Pavlu J., et al. Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: a phase I/II study in patients in complete haematological remission. Br. J. Haematol. 2007, 137:423-428.
133. Di Lorenzo G., et al. Docetaxel, vinorelbine, and zoledronic acid as first-line treatment in patients with hormone refractory prostate cancer: a phase II study. Eur. Urol. 2007, 52:1020-1027.
134. Di Lorenzo G., et al. Phase II trial of gemcitabine, prednisone, and zoledronic acid in pretreated patients with hormone refractory prostate cancer. Urology 2007, 69:347-351.
135. Mitsiades C.S., et al. Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablation-refractory prostate cancer. Anticancer Res. 2006, 26:3693-3700.
136. Lewis K.D., et al. A phase II open-label trial of apomine (SR-45023A) in patients with refractory melanoma. Invest. New Drugs 2006, 24:89-94.
137. Bertelli G., et al. Weekly docetaxel and zoledronic acid every 4 weeks in hormone-refractory prostate cancer patients. Cancer Chemother. Pharmacol. 2006, 57:46-51.
138. Figg W.D., et al. A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. J. Urol. 2005, 173:790-796.
139. Tiffany N.M., et al. Imatinib mesylate and zoledronic acid in androgen-independent prostate cancer. Urology 2004, 63:934-939.
140. Dearnaley D.P., et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J. Natl. Cancer Inst. 2003, 95:1300-1311.
141. Mardiak J., et al. Adjuvant clodronate therapy in patients with locally advanced breast cancer - long term results of a double blind randomized trial. Slovak Clodronate Collaborative Group. Neoplasma 2000, 47:177-180.
142. Peeters M., et al. Randomized phase 3 study of panitumumab with FOLFIRI vs FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC). Eur. J. Cancer Suppl. 2009, 7:9.
143. Van Cutsem E., et al. Kras status and efficacy in the Crystal Study: 1st-line treatment of patients with metastatic colorectal cancer (mCRC) receiving FOLFIRI with or without cetuximab. Ann. Oncol. 2008, 19(Suppl. 8):viii4.
144. Van Cutsem E., et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 2009, 360:1408-1417.
145. Di Fiore F., et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br. J. Cancer 2007, 96:1166-1169.
146. Frattini M., et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br. J. Cancer 2007, 97:1139-1145.
147. Hecht J.R., et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J. Clin. Oncol. 2009, 27:672-680.
148. Laurent-Puig P., et al. Kras mutations in colorectal cancer is a predictive factor of response and survival in patient treated with cetuximab. Ann. Oncol. 2007, 18:vii81.
149. Moroni M., et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005, 6:279-286.
150. Loupakis F., et al. Analysis of Pten expression and Kras mutations on primaries (prim) and metastases (mets) to predict benefit from cetuximab plus irinotecan (Cetiri) in metastatic colorectal cancer (mCRC) patients (pts). Ann. Oncol. 2008, 19(Suppl. 8):viii133-viii134.
151. Cappuzzo F., et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br. J. Cancer 2008, 99:83-89.
152. Finocchiaro G., et al. EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer. J. Clin. Oncol. 2007, 25:4021.
153. Freeman D.J., et al. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin. Colorectal Cancer 2008, 7:184-190.
154. Tabernero, J. et al. (2008) Correlation of efficacy to KRAS status (wt vs. mut) in patients (pts) with metastatic colorectal cancer (mCRC), treated with weekly (q1w) and q2w schedules of cetuximab combined with FOLFIRI. Presented at the 2008 Gastrointestinal Cancers symposium of the American Society of Clinical Oncology (ASCO), 25-27 January 2008, Orlando, USA.