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References
1. Reddy A, Kaelin WG. Using cancer genetics to guide the selection of anticancer drug targets. Curr Opin Pharmacol 2002;2: 366–373.
2. Workman P, Kaye SB. Translating basic cancer research into new cancer therapeutics. Trends Mole Med 2002;8:S1–S9.
3. Workman P. The impact of genomic and proteomic technologies on the development of new cancer drugs. Ann Oncol 2002;13:115–124.
4. Workman P. New drug targets for genomic cancer therapy: Successes, limitations, opportunities and future challenges. Curr Cancer Drug Targets 2001;1:33–47.
5. Workman P, Clarke PA. Innovative cancer drug targets: Genomics, transcriptomics and clinomics. Expert Opin Pharmacother 2001;2:911–915.
6. Workman P. Genomics and the second golden era of cancer drug development. Mol Biosyst 2005;1:17–26.
7. Workman P. Drugging the cancer kinome: Progress and challenges in developing personalized molecular cancer therapeutics. Cold Spring Harb Symp Quant Biol 2005;70:499–515.
8. Ponder BA. Cancer genetics. Nature 2001;411:336–341.
9. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.
10. Varmus H. The new era in cancer research. Science 2006;312:1162–1165.
11. Watson JP, Crick FHC. A structure for deoxyribose nucleic acid. Nature 1953;171:737–738.
12. Watson JP, Crick FHC. Genetical implications of the structure of deoxyribonucleic acid. Nature 1953;171:967.
13. Weinstein JN. ‘Omic’ and hypothesis-driven research in the molecular pharmacology of cancer. Curr Opin Pharmacol 2002;2:361–365.
14. Weinstein JN, Myers TG, O'Connor PM, et al. An information-intensive approach to the molecular pharmacology of cancer. Science 1997;275:343–349.
15. Workman P. Scoring a bull's-eye against cancer genome targets. Curr Opin Pharmacol 2001;1:342–352.
16. Downward J. The ins and outs of signaling. Nature 2001;411: 759–762.
17. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342–348.
18. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature 2001;411:366–374.
19. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789–799.
20. Hahn WC, Weinberg RA. A subway map for cancer pathways. Nature Rev Cancer 2002;2(5):331–341.
Molife R, Collins I, Workman P, Kaye SB. Rational drug design of small molecule anticancer agents: Early Clinical Development. In: The Cancer Handbook, Second Edition, Two Volume set (by Malcolm R. Alison (Editor-in-Chief), John Wiley and Sons, Inc, Chichester, UK, 2007. Available at: http://www.cancerhandbook.net.
22. Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 2002;297:63–64.
23. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006;3:448–457.
24. Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001;411:355–365.
25. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249–257.
26. Liotta LA, Kohn EC. The microenvironment of the tumor-host interface. Nature 2001;411:375–379.
27. Druker B. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mole Med 2002;8:S14–S18.
28. Opalinska JB, Gewirtz AM. Nucleic-acid therapeutics: Basic principles and recent applications. Nat Rev Drug Discov 2002;1:503–514.
29. Carter P. Improving the efficacy of antibody-based cancer therapies. Nature Rev Cancer 2001;1:118–129.
30. McCormick F. Cancer gene therapy: Fringe or cutting edge? Nature Rev Cancer 2001;1:130–141.
31. Rosenberg SA. Progress in human tumor immunology and immunotherapy. Nature 2001;411:380–384.
32. Sharp PA. RNA interference–2001. Genes Dev 2001;15:485–490.
33. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: New estimates of drug development costs. J Health Econ 2003;22:151–185.
34. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukaemia. Science 1960;132: 1497–1501.
35. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711–715.
36. Collins I, Workman P. New approaches to molecular cancer therapeutics. Nat Chem Biol 2006;2:689–700.
Garrett MD, Walton MI, McDonald E, Judson I, Workman P. The contemporary drug development process: Advances and challenges in preclinical and clinical development. In: Progress in cell cycle research, Vol. 5 (Meijer L, Jezequel A, and Roberge M, eds). Publisher-Editions Life in progress (2003).
38. Garrett MD, Workman P. Discovering novel chemotherapeutic drugs for the third millennium. Eur J Cancer 1999;35:2010–2030.
39. Futreal PA, Wooster R, Stratton MR. Somatic mutations in human cancer: Insights from resequencing the protein kinase gene family. Cold Spring Harb Symp Quant Biol 2005;70:43–49.
40. Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006;314:268–274.
41. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–954.
42. Benson JD, Chen YN, Cornell-Kennon SA, et al. Validating cancer drug targets. Nature 2006;441:451–456.
43. Fishman MC, Porter JA. Pharmaceuticals: A new grammar for drug discovery. Nature 2005;437:491–493.
44. Sharp S, Workman P. Inhibitors of the HSP90 molecular chaperone: Current status. Adv Cancer Res 2006;95:323–348.
45. Clarke PA, te Poele R, Wooster R, Workman P. Gene expression microarray analysis in cancer biology, pharmacology, and drug development: progress and potential. Biochem Pharmacol 2001;62:1311–1336.
46. Blackstock W, Mann M. A boundless future for proteomics? Trends Biotechnol 2001;2001:S1–S2.
47. Pandey A, Mann M. Proteomics to study genes and genomes. Nature 2000;405:837–846.
48. Kitano H. Computational systems biology. Nature 2002;420: 206–210.
49. Kitano H. Cancer as a robust system: Implications for anticancer therapy. Nat Rev Cancer 2004;4:227–235.
50. Nicholson JK, Connelly J, Lindon JC, Holmes E. Metabonomics: A platform for studying drug toxicity and gene function. Nat Rev Drug Discov 2002;1:153–161.
51. Nicholson JK. Global systems biology, personalized medicine and molecular epidemiology. Mol Syst Biol 2006;2:52.
52. Weinstein JN. Fishing expeditions. Science 1998;282:628–629.
53. Bajorath J. Integration of virtual and high-throughput screening. Nat Rev Drug Discov 2002;1:882–894.
54. Blundell TL, Jhoti H, Abell C. High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 2002;1:45–54.
55. Shuttleworth SJ, Connors RV, Fu J, et al. Design and synthesis of protein superfamily-targeted chemical libraries for lead identification and optimization. Curr Med Chem 2005;12:1239–1281.
56. Blundell TL. Structure-based drug design. Nature 1996;384: 23–26.
57. Smith NF, Hayes A, Nutley BP, Raynaud FI, Workman P. Evaluation of the cassette dosing approach for assessing the pharmacokinetics of geldanamycin analogues in mice. Cancer Chemother Pharmacol 2004;54:475–486.
58. Raynaud FI, Fischer PM, Nutley BP, Goddard PM, Lane DP, Workman P. Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis. Mol Cancer Ther 2004;3:353–362.
59. Smith NF, Hayes A, James K, et al. Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors. Mol Cancer Ther 2006;5:1628–1637.
60. Raynaud FI, Whittaker SR, Fischer PM, et al. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 2005;11:4875–4887.
61. Banerji U, Walton M, Raynaud F, et al. Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 2005;11:7023–7032.
62. Sarker D, Workman P. Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res 2006;96:213–268.
63. Sharpless NE, DePinho RA. The mighty mouse: Genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 2006;5:741–754.
64. Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer drug development. Cancer Res 2006;66: 3351–3354.
65. Sawyers CL. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev 2003;17:2998–3010.
DeVita VT, Hellman S, Rosenberg SA. Cancer. principles and practice of oncology. DeVita VT, Hellman S, .Rosenberg SA (eds.). Philadelphia. Lippincott-Raven. 2001.
67. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.
68. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: A review of validation studies on tumour assessment. Eur J Cancer 2006;42:1031–1039.
69. Harries M, Smith I. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer 2002;9:75–85.
70. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337: 1021–1028.
71. Kopec JA, Abrahamowicz M, Esdaile JM. Randomized discontinuation trials: Utility and efficiency. J Clin Epidemiol 1993;46:959–971.
72. Workman P. Challenges of PK/PD measurements in modern drug development. Eur J Cancer 2002;38:2189.
73. Workman P. How much gets there and what does it do?: The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development. Curr Pharma Design 2003; 9: 891–902.
74. Workman P. Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: Unfolding the relationship between pharmacokinetics and pharmacodynamics. Mol Cancer Ther 2003;2:131–138.
75. Parulekar WR, Eisenhauer EA. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: Theory and practice. J Natl Cancer Inst 2004;96:990–997.
76. Schilsky RL, Taube SE. Tumor markers as clinical cancer tests—are we there yet? Semin Oncol 2002;29:211–212.
77. Workman P, Aboagye EO, Chung YL, et al. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 2006;98:580–598.
78. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781–791.
79. Padhani AR. Functional MRI for anticancer therapy assessment. Eur J Cancer 2002;38:2116–2127.
80. O'Donnell A, Padhani A, Hayes C, et al. A phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points. Br J Cancer 2005;93:876–883.
81. Evelhoch J, Garwood M, Vigneron D, et al. Expanding the use of magnetic resonance in the assessment of tumor response to therapy: Workshop report. Cancer Res 2005;65:7041–7044.
82. Galbraith SM, Rustin GJ, Lodge MA, et al. Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol 2002;20:3826–3840.
83. Galbraith SM, Maxwell RJ, Lodge MA, et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 2003;21:2831–2842.
84. Evelhoch JL, LoRusso PM, He Z, et al. Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 2004;10:3650–3657.
85. Rehman S, Jayson GC. Molecular imaging of antiangiogenic agents. Oncologist 2005;10:92–103.
86. Artemov D. Molecular magnetic resonance imaging with targeted contrast agents. J Cell Biochem 2003;90:518–524.
87. Weissleder R, Moore A, Mahmood U, et al. In vivo magnetic resonance imaging of transgene expression. Nat Med 2000;6:351–355.
88. Louie A, Meade T. Recent advances in MRI: Novel contrast agents shed light on in vivo biochemistry. New Technologies for Life Sciences: A Trends Guide 2000;2000:7–11.
89. Weissleder R, Mahmood U. Molecular imaging. Radiol 2001;219:316–333.
90. Schellenberger EA, Bogdanov A, Jr., Hogemann D, Tait J, Weissleder R, Josephson L. Annexin V-CLIO: A nanoparticle for detecting apoptosis by MRI. Mol Imaging 2002;1:102–107.
91. Galons JP, Altbach MI, Paine-Murrieta GD, Taylor CW, Gillies RJ. Early increases in breast tumor xenograft water mobility in response to paclitaxel therapy detected by non-invasive diffusion magnetic resonance imaging. Neoplasia 1999;1:113–117.
92. Dzik-Jurasz A, Domenig C, George M, et al. Diffusion MRI for prediction of response of rectal cancer to chemoradiation. Lancet 2002;360:307–308.
93. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 2002;1:493–502.
94. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3–7.
95. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290–293.
96. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000;96:3343–3356.
97. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037.
98. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–1042.
National Institute for Clinical Excellence. The effectiveness and cost-effectiveness of imatinib (STI-571) in chronic myeloid leukaemia. 2002. The Stationary Office, London.
100. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–652.
101. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002;100:1965–1971.
102. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study. Blood 2002;99:3530–3539.
103. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 2002;99:1928–1937.
104. Braziel RM, Launder TM, Druker BJ, et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months’ experience. Blood 2002;100:435–441.
105. Kantarjian HM, Cortes JE, O'Brien S, et al. Imatinib mesylate therapy in newly-diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: High incidence of early complete and major cytogenetic responses. Blood 2002;101:97–100.
106. Atallah E, Talpaz M, O'Brien S, et al. Chronic myelogenous leukemia in T cell lymphoid blastic phase achieving durable complete cytogenetic and molecular remission with imatinib mesylate (STI571; Gleevec) therapy. Cancer 2002;94:2996–2999.
107. Kantarjian HM, Talpaz M, O'Brien S, et al. Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: Follow-up results. Clin Cancer Res 2002;8:2177–2187.
108. Kantarjian HM, O'Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res 2002;8:2167–2176.
109. Kantarjian HM, Cortes J, O'Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002;99:3547–3553.
110. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876–880.
111. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16:2190–196.
112. Branford S, Hughes TP, Rudzki Z. Dual transcription of b2a2 and b3a2 BCR-ABL transcripts in chronic myeloid leukaemia is confined to patients with a linked polymorphism within the BCR gene. Br J Haematol 2002;117:875–877.
113. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 2002;100:1014–1018.
114. Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci USA 2002;99:10700–10705.
115. von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: A prospective study. Lancet 2002;359:487–491.
116. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117–125.
117. Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia 2003;17: 2401–2409.
118. Soverini S, Martinelli G, Amabile M, et al. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib. Clin Chem 2004;50:1205–1213.
119. Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood 2002;100:3041–3044.
120. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000;289:1938–1942.
121. Corbin AS, Buchdunger E, Pascal F, Druker BJ. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem 2002;277:32214–32219.
122. Martinelli G, Soverini S, Rosti G, Cilloni D, Baccarani M. New tyrosine kinase inhibitors in chronic myeloid leukemia. Haematologica 2005;90:534–541.
123. Corbin AS, La RP, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 2003;101:4611–4614.
124. Gambacorti-Passerini C, Piazza R, D'Incalci M. Bcr-Abl mutations, resistance to imatinib, and imatinib plasma levels. Blood 2003;102:1933–1934.
125. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:4500–4505.
126. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005;7:129–141.
127. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2002;62:4236–4243.
128. Manley PW, Breitenstein W, Bruggen J, et al. Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases. Bioorg Med Chem Lett 2004;14:5793–5797.
129. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542–2551.
130. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401.
Coutre S, Martinelli G, Dombret H, et al. Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 ‘START-L’ study. Proc Am Soc Clin Oncol 2006;24:No 18S (abstract 6528).
Talpaz M, Apperley JF, Kim DW et al. Dasatinib (D) in patients with accelerated phase chronic myeloid leukemia (AP-CML) who are resistant or intolerant to imatinib: Results of the CA180005 ‘START-A’ study. Proc Am Soc Clin Oncol 2006;24:No 18S(abstract 6526).
Shah NP, Rousselot P, Pasquini R et al. Dasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial. Proc Am Soc Clin Oncol 2006;24:No 18S (abstract 6507).
Hochhaus A, Kantarjian H, Baccarani M et al. Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 ‘START-C’ Study. Proc Am Soc Clin Oncol 2006;24:page number (abstract 6508).
135. Deeks SG. Antiretroviral treatment of HIV infected adults. Br Med J 2006;332:1489.
136. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577–580.
137. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–710.
138. Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterol 2003;125:660–667.
139. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.
140. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 2001;358:1421–1423.
141. van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: A report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38: S83-S87.
142. Verweij J, van OA, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39:2006–2011.
Rankin C, Von Mehren M, Blanke C, et al. Dose effect of imatinib (IM) in patients (pts) with metastatic GIST - Phase III Sarcoma Group Study S0033. Proc Am Soc Clin Onco 2004;22:No 14S(abstract 9005).
144. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127–1134.
145. Dagher R, Cohen M, Williams G, et al. Approval summary: Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002;8:3034–3038.
146. Zalcberg JR, Verweij J, Casali PG, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005;41:1751–1757.
147. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342–4349.
148. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813–3825.
149. Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40: 689–695.
150. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res 2004;10:3282–3290.
151. Frolov A, Chahwan S, Ochs M, et al. Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. Mol Cancer Ther 2003;2:699–709.
152. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–710.
153. Debiec-Rychter M, Sciot R, Le Cense A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006;42:1093–1103.
Fletcher JA, Corless CL, Dimitrijevic S, et al. Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol 2003;22:(abstract 3275).
155. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006;368:1329–1338.
156. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–225.
157. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.
158. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.
159. Bruns CJ, Solorzano CC, Harbison MT, et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000;60: 2926–2935.
160. Lu Z, Jiang G, Blume-Jensen P, Hunter T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 2001;21:4016–4031.
161. Brabender J, Danenberg KD, Metzger R, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res 2001;7:1850–1855.
162. Meyers MB, Shen WP, Spengler BA, et al. Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem 1988;38:87–97.
163. de Bono J, Rowinsky E. The ErbB receptor family: A therapeutic target for cancer. Trends Mol Med 2002;8:S19–S26.
164. Ciardiello F, Tortora G. Anti-epidermal growth factor receptor drugs in cancer therapy. Expert Opin Investig Drugs 2002;11:755–768.
165. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002;20:1S–13S.
166. Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.
167. Moyer JD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 1997;57:4838–4848.
168. Friedmann B, Caplin M, Hartley JA, Hochhauser D. Modulation of DNA repair in vitro after treatment with chemotherapeutic agents by the epidermal growth factor receptor inhibitor gefitinib (ZD1839). Clin Cancer Res 2004;10:6476–6486.
169. 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 2002;20:4292–4302.
170. Raben D, Helfrich BA, Chan D, Johnson G, Bunn PA, Jr. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 2002;29:37–46.
171. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 2002;20:2240–2250.
172. Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000;18:904–914.
173. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267–3279.
174. Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 2005;10:345–356.
175. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002;7:2–8.
176. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 2003;21:2237–2246.
177. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 2006; 95:998–1004.
178. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factior receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 2003; 290:2149–2158.
179. Cohen EEW, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent and metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21:1980–1987.
180. Giaccone G, Johnson DH, Manegold C, et al. A phase III clinical trial of ZD1839 (“Iressa”) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (INTACT 1). Ann Oncol 2002;13:2 (abstract 40).
181. Johnson DH, Herbst R, Giaccone G, et al. ZD1839 (“Iressa”) in combination with paclitaxel & carboplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC): Results from a phase III clinical trial (INTACT 2). Ann Oncol 2002;13:127 (abstract 4680).
182. Wilkinson E. Surprise phase III failure for ZD1839. Lancet Oncol 2002;3:583.
Gatzemeier U, Pluzanska A, Szczesna A, et al. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004;22:No 14S(abstract 7010).
184. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–5899.
185. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.
186. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–1537.
187. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
188. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.
189. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–346.
190. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900–5909.
191. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163–1167.
192. Dowell JE, Minna JD. EGFR mutations and molecularly targeted therapy: A new era in the treatment of lung cancer. Nat Clin Pract Oncol 2006;3:170–171.
193. Baselga J. Targeting tyrosine kinases in cancer: The second wave. Science 2006;3:1175–1178.
Miller VA, Zakowski M, Riely GJ et al. EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): Results of a prospective phase II trial. Proc Am Soc Clin Oncol. 2006;24:No 18S(abstract 7003).
195. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
196. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.
197. Kiyota A, Shintani S, Mihara M, et al. Anti-epidermal growth factor receptor monoclonal antibody 225 upregulates p27(KIP1) and p15(INK4B) and induces G1 arrest in oral squamous carcinoma cell lines. Oncol 2002;63:92–98.
198. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999;59:1935–1940.
199. Huang SM, Li J, Armstrong EA, Harari PM. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 2002;62:4300–4306.
200. Shin DM, Donato NJ, Perez-Soler R, et al. Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 2001;7:1204–1213.
Trigo J, Hitt R, Koralewski P, et al. Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study. Proc Am Soc Clin Oncol 2004;22:No 14S(abstract 5502).
Vermorken J, Bourhis J, Trigo M, et al. Cetuximab (Erbitux®) in recurrent/metastatic (R&M) squamous cell carcinoma of the head and neck (SCCHN) refractory to first-line platinum-based therapies. Proc Am Soc Clin Oncol 2005;23:No 16S(abstract 5505).
203. Bonner JA, Harari PM, Giralt J,et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.
204. Saltz LB, Meropol NJ, Loehrer PJ, Sr., Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208.
205. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
Lang I, J Zaluski, Changchien CR, et al. Cetuximab with irinotecan in first-line treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC): Preliminary safety results (CRYSTAL). Proc Am Soc Clin Oncol 2006;24:No 18 S(abstract 3555).
Abubakr Y, Eng C, Pautret V, et al. Cetuximab plus irinotecan for metastatic colorectal cancer (mCRC): Safety analysis of 800 patients in a randomized phase III trial (EPIC). Proc Am Soc Clin Oncol 2006;24: No. 18S (abstract 3556).
Jennis A, Polikoff J, Mitchell E, et al. Erbitux (Cetuximab) Plus FOLFOX for Colorectal Cancer (EXPLORE): Preliminary efficacy analysis of a randomized phase III trial. Pro Am Soc Clin Oncol 2005;23:No.16S(abstract 3574).
Kelly K, Hanna N, Rosenberg A, et al. A multi-centered phase I/II study of cetuximab in combination with paclitaxel and carboplatin in untreated patients with stage IV non-small cell lung cancer. Proc Am Soc Clin Oncol 2003;22: (abstract 2592).
Robert F, Blumenschein G, Dicke K, et al. Phase Ib/IIa study of anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, in combination with gemcitabine/carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2003;22: (abstract 2587).
Rosell R, Daniel C, Ramlau R, et al. Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004;22: No. 14S(abstract 7012).
Figlin RA, Belldegrun AS, Crawford J, et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: Phase 1 clinical results. Proc Am Soc Clin Oncol 2002;21: (abstract 35).
213. Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer 2006;6:29–31.
214. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.
215. Kumar PS, Pegram M. Targeting HER2 Epitopes. Semin Oncol 2006;33:386–391.
216. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17: 2639–2648.
217. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999;26:78–83.
218. Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR. Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: A phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21:283–290.
219. Swanton C, Futreal A, Eisen T. Her2-targeted therapies in Non-small cell lung cancer. Clin Cancer Res 2006; 12 (14p2):4377s–4383s.
220. Lara PM Jr, Laptalo L, Longmate J, et al. Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: A California Cancer Consortium screening and phase II trial.Clin Lung Cancer. 2004;5(4):231–236.
221. Krug LM, Miller VA, Patel J, et al. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced non small cell lung carcinoma. Cancer 2005; 104 (10):2149–2155.
222. Lara PN, Jr., Chee KG, Longmate J, et al. Trastuzumab plus docetaxel in HER-2/ neu positive prostate carcinoma: Final results from the California Cancer Consortium Screening and Phase II trial. Cancer, 2004;100 (10):2125–2131.
223. Zinner RG, Glisson BS, Fosella FV, et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2- overexpressing, untreated, advanced non-small cell lung cancer: Report of a phase II trial and findngs regarding optimal identification of patients with Her2- overexpressing disease. Lung Cancer 2004;44 (1):99–110.
224. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004;15(1):19–27.
225. Eiermann W. Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: Pivotal trial data. Ann Oncol 2001;12:S57–S62.
226. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.
227. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.
228. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820.
229. Slamon D, Eiermann W, Robert N, et al.. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 2005; 94:S5 (abstract 1).
230. Jarvinen TA, Tanner M, Rantanen V, et al. Amplification and deletion of topoisomerase IIα associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 2000;156: 839–847.
231. Tanner M, Isola J, Wiklund T, et al. Topoisomerase IIα gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006;24:2428–2436.
232. Moasser MM, Basso A, Averbuch SD, Rosen N. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 2001;61:7184–7188.
233. Normanno N, Campiglio M, De Luca A, et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002;13:65–72.
234. Ye D, Mendelsohn J, Fan Z. Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a human-mouse chimeric anti-EGF receptor mAb C225. Oncogene 1999;18:731–738.
235. Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.
236. Zhou Y, Li S, Hu YP, et al. Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis. Cancer Res 2006;66:404–411.
237. Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001;1:85–94.
238. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002;21:6255–6263.
239. Burris HA, III, Hurwitz HI, Dees EC, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 2005;23:5305–5313.
Versola M, Burris HA, Jones S, et al. Clinical activity of GW572016 in EGF10003 in patients with solid tumors. Proc Am Soc Clin Oncol 2004;22:No 14S (abstract 3047).
Blackwell KL, Burstein H, Pegram M, et al.. Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer. Proc Am Soc Clin Oncol 2005; 23: No 16S (abstract 3004).
Gomez HL, Chavez MA, Doual DC et al. A phase II, randomized trial using the small molecule tyrosine kinase inhibitor lapatinib as a first-line treatment in patients with FISH positive advanced or metastatic breast cancer. Proc Am Soc Clin Oncol 2005; 23: No 16S (abstract 3046).
Spector NL, Blackwell k, Hurley J, et al. EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response. Proc Am Soc Clin Oncol 2006;24: No 18S (abstract 502).
Lin NU, Carey A, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. Proc Am Soc Clin Oncol 2006;24:No 18S (abstract 503).
Ravaud A, Gardner J, Hawkins R, et al. Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol 2006; 24: No. 18S (abstract 4502).
Mom CH, Eskens F, Gietema JA, et al. Phase 1 study with BIBW 2992, an irreversible dual tyrosine kinase inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) in a 2 week on 2 week off schedule. Proc Am Soc Clin Oncol 2006;24: No. 18S (abstract 3025).
Lewis N, Marshall J, Amelsberg A, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2006;24:No 18S (abstract 3091).
Shaw H, Plummer R, Vidal L, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with an advanced solid tumours. Proc Am Soc Clin Oncol 2006;24:No. 18S (abstract 3027).
Agus DB, Terlizzi E, Stopfer P, et al. A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours. Proc Am Soc Clin Oncol 2006;24:No. 18S (abstrct 2074).
Wong KK, Fracasso M, Bukowski RM, et al.. HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors. Proc Am Soc Clin Oncol 2006;24: No. 18S (abstract 3018).
Rinehart JJ, Wilding G, Willson J, et al. A phase 1 clinical and pharmacokinetic study of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2002; (abstract 41).
252. Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 2001;28:80–85.
253. Campos S, Hamid O, Seiden MV, et al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J Clin Oncol 2005;23:5597–5604.
254. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127–137.
255. Schaefer G, Fitzpatrick VD, Sliwkowski MX. Gamma-heregulin: A novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997;15:1385–1394.
256. Mendoza N, Phillips GL, Silva J, Schwall R, Wickramasinghe D. Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res 2002;62:5485–5488.
257. Takai N, Jain A, Kawamata N, et al. 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth. Cancer 2005;104:2701–2708.
258. Jackson JG, St Clair P, Sliwkowski MX, Brattain MG. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res 2004;64:2601–2609.
259. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005;23:2534–2543.
260. Malik MA. Dose response studies of recombinant humanized monoclonal antibody 2C4 in tumor xenograft models. Proc Am Assoc Cancer Res 2003;44:150 (abstract 773).
261. de Bono JS, Bellmunt J, Attard G, et al. Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 2007;25(3):257–262.
262. Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: Potential predictive relationship with tumor HER2 activation status. J Clin Oncol 2006;24:4324–4332.
263. Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin Cancer Res 2006;12:4441s–4445s.
Agus DB, Sweeney CJ, Morris M, et al. Efficacy and safety of single agent pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in hormone refractory prostate cancer after failure of taxane-based therapy. Proc Am Soc Clin Oncol 2005;23:No. 16S (abstract 4624) .
265. Favelyukis S, Till JH, Hubbard SR, Miller WT. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol 2001;8:1058–1063.
Attard G. Fong PC, Rea M, et al. Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer. Proc Am Soc Clin Oncol 2006;24: No. 18S (abstract 3023).
267. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup Protocol. Blood 2002; 100(13):4298–302.
268. Degos L, Wang ZY. All trans retinoic acid in acute promyelocytic leukemia. Oncogene 2001;20:7140–7145.
269. Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol 2001;38:13–25.
270. Fenaux P, Chevret S, Guerci A, et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia 2000;14:1371–1377.
271. Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature 1983;303(5916):396–400.
272. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11–22.
273. Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989;57:1167–1177.
274. Liu A, Du W, Liu JP, Jessell TM, Prendergast GC. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol Cell Biol 2000;20:6105–6113.
275. Jiang K, Coppola D, Crespo NC, et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 2000;20:139–148.
276. Ashar HR, James L, Gray K, et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem 2000;275:30451–30457.
277. Johnston SR, Hickish T, Ellis P, 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.
278. Adjei AA, Mauer A, Bruzek L, 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.
279. Cohen SJ, Ho L, Ranganathan S, 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.
Johnston S, Semiglazov V, Manikas G, et al. A randomised, blinded, phase I study of ripifarrib combined with tetrozole in the treatment of advanced breast cancer that has progressed with antioestrogen therapy. In: Breast Cancer Res Treat. Vol 94. San Antonio (TX): San Antonio Breast Cancer Symposium; 2005.
281. Rao S, Cunningham D, de GA, 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.
282. Van Cutsen E, van de Velds H, Karasek P 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.
Lancet JE, Gojo I, Gotlib J, et al. A phase II study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2006;04–014357v1.
284. Schreck R, Rapp UR. Raf kinases: Oncogenesis and drug discovery. Int J Cancer 2006;119:2261–2271.
285. Sridhar SS, Hedley D, Siu LL. Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther 2005;4:677–685.
286. Beeram M, Patnaik A, Rowinsky EK. Raf: A strategic target for therapeutic development against cancer. J Clin Oncol 2005;23:6771–6790.
287. Tolcher AW, Reyno L, Venner PM, et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2002;8:2530–2355.
288. Cripps MC, Figueredo AT, Oza AM, et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: A National Cancer Institute of Canada clinical trials group study. Clin Cancer Res 2002;8:2188–2192.
289. Oza AM, Elit L, Swenerton K, et al. Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: An NCIC clinical trials group study (NCIC IND.116). Gynecol Oncol 2003;89:129–133.
290. Rudin CM, Marshall JL, Huang CH, et al. Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: A phase I study. Clin Cancer Res 2004;10:7244–7251.
291. Dritschilo A, Huang CH, Rudin CM, et al. Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies. Clin Cancer Res 2006;12:1251–1259.
292. Grbovic OM, Basso AD, Sawai A, et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc Natl Acad Sci USA 2006;103:57–62.
293. da Rocha DS, Friedlos F, Light Y, Springer C, Workman P, Marais R. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res 2005;65:10686–10691.
294. Sebolt-Leopold JS, Dudley DT, Herrera R, et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999;5:810–816.
295. LoRusso PM, Adjei AA, Varterasian M, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23:5281–5293.
296. Rinehart J, Adjei AA, LoRusso PM, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004;22:4456–4462.
297. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004;4:937–947.
298. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med 2006;38:200–211.
299. Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006;439:358–362.
300. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.
301. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
302. Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol 2006;18:77–82.
303. Wipf P, Halter RJ. Chemistry and biology of wortmannin. Org Biomol Chem 2005;3:2053–2061.
304. Vlahos CJ, Stancato LF. Inhibitors of cellular signaling targets: Designs and limitations. Methods Mol Biol 2004;273:87–102.
305. Hayakawa M, Kaizawa H, Kawaguchi K, et al. Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem 2007;15:403–412.
306. Hayakawa M, Kaizawa H, Moritomo H, et al. Synthesis and biological evaluation of pyrido [3′,2′:4,5]furo[3,2-d] pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem Lett 2007 May 1:17(9):2348–2442.
307. Workman P, Clarke PA, Guillard S, Raynaud FI. Drugging the PI3 kinome. Nat Biotechnol 2006;24:794–796.
308. Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341–349.
309. Yaguchi S, Fukui Y, Koshimizu I, et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 2006;98:545–556.
310. Knight ZA, Gonzalez B, Feldman ME, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733–747.
311. Foukas LC, Claret M, Pearce W, et al. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006;441:366–370.
312. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5:671–688.
313. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975;28:721–726.
314. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): Mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998;31:335–340.
O'Reilly T, Vaxelaire J, Muller M, et al. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. 2002; 43: (abstract71.)
316. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004; 64(1): 252–261
O'Donnell A, Faivre S, Judson I, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumours. Proc Am Soc Clin Oncol 2003;22:(abstract 803).
Tabernero J, Rojo F, Burris H, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors. Proc Am Soc Clin Oncol 2005;23:No 16S (abstract 3007).
Pacey S, Rea D, Steven N, et al. Results of a phase 1 clinical trial investigating a combination of the oral mTOR-inhibitor Everolimus (E, RAD001) and Gemcitabine (GEM) in patients (pts) with advanced cancers. Proc Am Soc Clin Oncol 2004;22:No. 14S (abstract 3120).
320. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004;22:2336–2347.
321. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006;12:5755–5763.
Oza AM, Elit L, Biagi J, et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer–NCIC IND 160. Proc Am Soc Clin Oncol 2006;24:No. 18S (abstract 3003).
323. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909–918.
324. Chan S, Scheulen ME, Johnston S. et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314–5322.
325. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group Study. J Clin Oncol 2005;23:5294–5304.
326. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347–5356.
Desai AA, Janisch L, Berk LR, et al. A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis. Proc Am Soc Clin Oncol 2004;22:No. 14S (abstract 3150).
Mita MM, Rowinsky EK, Goldston ML, et al. Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies. Proc Am Soc Clin Oncol 2004;22:No. 14S (abstract 3076).
Perotti A, Maur M, Vigano L, et al. Phase Ib pharmacokinetic (PK) and pharmacodynamic (PD) study to define the optimal dose for combining the mTOR inhibitor AP23573 with capecitabine (CAPE). Proc Am Soc Clin Oncol 2006;24:No. 18S (abstract 3065).
Feldman E, Giles F, Roboz G, et al. A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies. Proc Am Soc Clin Oncol 2005;23: No. 16S (abstract 6631).
Chawla SP, Tolcher AW, Staddon AP, et al. Updated results of a phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas. Proc Am Soc Clin Oncol 2006;24: No. 18S (abstract 9505).
332. deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004;10:8059–8067.
333. Kokubo Y, Gemma A, Noro R, et al. Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Br J Cancer 2005;92:1711–1719.
334. Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 2003;3:233–245.
335. Barbacid M, Ortega S, Sotillo R, et al. Cell cycle and cancer: Genetic analysis of the role of cyclin-dependent kinases. Cold Spring Harb Symp Quant Biol 2005;70:233–240.
336. Byrd JC, Peterson BL, Gabrilove J, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: Results from Cancer and Leukemia Group B study 19805. Clin Cancer Res 2005;11:4176–4181.
337. Flinn IW, Byrd JC, Bartlett N, et al. Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leuk Res 2005;29:1253–1257.
338. Lin TS, Howard OM, Neuberg DS, Kim HH, Shipp MA. Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma. Leuk Lymphoma 2002;43:793–797.
339. Yu C, Krystal G, Dent P, et al. Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells. Clin Cancer Res 2002;8:2976–2984.
340. Van Veldhuizen PJ, Faulkner JR, Lara PN, et al. A phase II study of flavopiridol in patients with advanced renal cell carcinoma: Results of Southwest Oncology Group Trial 0109. Cancer Chemother Pharmacol 2005;56:39–45.
341. Stadler WM, Vogelzang NJ, Amato R, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: A University of Chicago Phase II Consortium study. J Clin Oncol 2000;18:371–375.
342. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427–1438.
343. VanderWel SN, Harvey PJ, McNamara DJ, et al. Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J Med Chem 2005;48:2371–2387.
344. Toogood PL, Harvey PJ, Repine JT, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005;48:2388–2406.
345. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24:1770–1783.
346. Benson C, White J, de Bono JS, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer 2007; 96(1):29–37.
Pierga JS, Faivre K, Vera, et al. A phase I and pharmacokinetic (PK) trial of CYC202, a novel oral cyclin-dependent kinase (CDK) inhibitor, in patients (pts) with advanced solid tumors. Proc Am Soc Clin Oncol 2003;22: (abstract 840).
348. Whittaker SR, Walton MI, Garrett MD, Workman P. The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 2004;64:262–272.
349. Tan AR, Yang X, Berman A, et al. Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res 2004;10:5038–5047.
350. Haddad RI, Weinstein LJ, Wieczorek TJ, et al. A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: Modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor. Clin Cancer Res 2004;10:4680–4687.
351. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 2002;8:S55–S61.
352. Schulte TW, Blagosklonny MV, Romanova L, et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol Cell Biol 1996;16:5839–5845.
353. Miller P, Schnur RC, Barbacci E, Moyer MP, Moyer JD. Binding of benzoquinoid ansamycins to p100 correlates with their ability to deplete the erbB2 gene product p185. Biochem Biophys Res Commun 1994;201:1313–1319.
354. Miller P, DiOrio C, Moyer M, et al. Depletion of the erbB-2 gene product p185 by benzoquinoid ansamycins. Cancer Res 1994;54:2724–2730.
355. Stepanova L, Leng X, Parker SB, Harper JW. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev 1996;10:1491–1502.
356. Blagosklonny MV, Toretsky J, Bohen S, Neckers L. Mutant conformation of p53 translated in vitro or in vivo requires functional HSP90. Proc Natl Acad Sci USA 1996;93:8379–8383.
357. Haendler B, Schuttke I, Schleuning WD. Androgen receptor signalling: Comparative analysis of androgen response elements and implication of heat-shock protein 90 and 14–3-3eta. Mol Cell Endocrinol 2001;173:63–73.
358. Bagatell R, Khan O, Paine-Murrieta G, Taylor CW, Akinaga S, Whitesell L. Destabilization of steroid receptors by heat shock protein 90-binding drugs: A ligand-independent approach to hormonal therapy of breast cancer. Clin Cancer Res 2001;7:2076–2084.
359. Fang Y, Fliss AE, Robins DM, Caplan AJ. Hsp90 regulates androgen receptor hormone binding affinity in vivo. J Biol Chem 1996;271:28697–28702.
360. Segnitz B, Gehring U. The function of steroid hormone receptors is inhibited by the hsp90-specific compound geldanamycin. J Biol Chem 1997;272:18694–18701.
361. Roe SM, Prodromou C, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 1999;42:260–266.
362. Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 1997;90:65–75.
363. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 1995;36:305–315.
364. Clarke PA, Hostein I, Banerji U, et al. Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone. Oncogene 2000;19:4125–4133.
365. Panaretou B, Siligardi G, Meyer P, et al. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol Cell 2002;10:1307–1318.
366. Kelland LR, Sharp SY, Rogers PM, Myers TG, Workman P. DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst 1999;91:1940–1949.
367. Chung Y-L, Troy H, Banerji U, et al. Magnetic Resonance Spectroscopic pharmacodynamic markers of Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG) in human colon cancer models. JNCI 2003; 95:1624–1633.
368. Banerji U, Walton M, Raynaud F, et al. PK-PD relationships for the HSP90 molecular chaperone inhibitor 17AAG in human ovarian cancer xenograft models. Clin Cancer Res. 2005; 11(19 Pt 1):7023–7032.
369. Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 2005;23:4152–4161.
370. Ramanathan RK, Trump DL, Eiseman JL, et al. Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin Cancer Res 2005;11:3385–3391.
371. Grem JL, Morrison G, Guo XD, et al. Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 2005;23:1885–1893.
372. Goetz MP, Toft D, Reid J, et al. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 2005;23:1078–1087.
373. Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 2005;23:4152–4161.
374. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 2003;63:2139–2144.
374a. Sain N, Krishnan B, Ormerod M, et al. Potentia of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxy geldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 2006;5(5):1197–1208.
375. Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin Biol Ther 2002;2:3–24.
376. Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 2006;49:4606–4615.
377. Sharp SY, Prodrornou C, Boxall K, et al. Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther 2007: 6(4) 1198–1211.
378. McDonald E, Jones K, Brough PA, Drysdale MJ, Workman P. Discovery and development of pyrazole-scaffold Hsp90 inhibitors. Curr Top Med Chem 2006;6:1193–1203.
379. McDonald E, Workman P, Jones K. Inhibitors of the HSP90 molecular chaperone: Attacking the master regulator in cancer. Curr Top Med Chem 2006;6:1091–1107.
380. Barril X, Beswick MC, Collier A, et al. 4-Amino derivatives of the Hsp90 inhibitor CCT018159. Bioorg Med Chem Lett 2006;16:2543–2548.
381. Cheung KM, Matthews TP, James K, et al. The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors. Bioorg Med Chem Lett 2005;15:3338–3343.
382. Dymock BW, Barril X, Brough PA, et al. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem 2005; 48:4212–4215.
383. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–974.
384. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401–410.
385. Folkman J, Hochberg M. Self-regulation of growth in three dimensions. J Exp Med 1973;138:745–753.
386. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795–803.
387. Millauer B, Wizigmann-Voos S, Schnurch H, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993;72:835–846.
388. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721–732.
389. Kabbinavar F, Hurwitz HI, 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 2003;21:60–65.
390. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
391. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184–2191.
392. Sandler AB, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N Engl J Med. 2006;355(24):2542–2550.
393. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23:792–799.
394. Yang JC, Haworth L, Sherry RM, 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.
395. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
396. Gordon MS, 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 2001;19:843–850.
397. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.
398. Yang JC, Haworth L, Sherry RM, 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.
Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Proc Am Soc Clin Oncol 2005;23:No.16S (abstract 2).
400. Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 199656:2299–2301.
401. Mendel DB, Laird AD, Xin X, 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.
402. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25–35.
403. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516–2524.
404. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16–24.
405. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–124.
406. Wilhelm SM, Carter C, Tang L, 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.
407. Awada A, Hendlisz A, Gil T, et al. Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer 2005;92:1855–1861.
408. Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 2005;11:5472–5480.
409. Moore M, Hirte HW, Siu L, et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43–9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol 2005;16:1688–1694.
410. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965–972.
411. Ratain MJ, Eisen T, Stadler WM, 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.
412. Escudier B, Eisen T, Stadler WM, et al Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–134.
413. Ratain MJ, Eisen T, Stadler WM, 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.
414. Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 2006;3:24–40.
415. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 2001;7:987–989.
416. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends Genet 2000;16:168–174.
417. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2005;2:S4–S11.
418. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006;5:769–784.
419. Kelly WK, Richon VM, O'Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 2003;9: 3578–3588.
420. Kelly WK, O'Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005;23: 3923–3931.
421. O'Connor OA, Heaney ML, Schwartz L, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006;24:166–173.
422. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109(1):31–39.
423. Piekarz RL, Frye AR, Wright JJ, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 2006;12:3762–3773.
424. Jose B, Okamura S, Kato T, Nishino N, Sumida Y, Yoshida M. Toward an HDAC6 inhibitor: Synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from alpha-tubulin sequence. Bioorg Med Chem 2004;12: 1351–1356.
425. Schreiber V, Dantzer F, Ame JC, et al. Poly(ADP-ribose): Novel functions for an old molecule. Nat Rev Mol Cell Biol 2006;7:517–528.
426. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 2006;66:8109–8115.
427. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917–921.
Fong PC, Spicer J, Reade S, et al. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of a small molecule inhibitor of Poly ADP-Ribose Polymerase (PARP), KU-0059436 (Ku) in patients (p) with advanced tumours. Proc Am Soc Clin Oncol 2006;24: No. 18S (abstact 3022).
429. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction - a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006;3(8):448–457.
430. Mills GB, Lu Y, Kohn EC. Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:10031–10033.
431. Fox E, Curt GA, Balis FM. Clinical trial design for target-based therapy. Oncologist 2002;7:401–409.
432. Stroobants S, Goeminne J, Seegers M et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec®). Eur J of Cancer 2003; 39:2012–2020.
van Oosterom A, Reicharat P, Blay J.-Y. A phase I/II trial of the oral MDR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: Study update. Proc Am Soc Clin Oncol 2005; 23 No. 16S (Abstract 9033).
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Reid, A.H., Baird, R., Workman, P. (2008). Emerging Molecular Therapies: Drugs Interfering With Signal Transduction Pathways. In: Bronchud, M.H., Foote, M.A., Giaccone, G., Olopade, O., Workman, P. (eds) Principles of Molecular Oncology. Humana Press. https://doi.org/10.1007/978-1-59745-470-4_17
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DOI: https://doi.org/10.1007/978-1-59745-470-4_17
Publisher Name: Humana Press
Print ISBN: 978-1-934115-25-1
Online ISBN: 978-1-59745-470-4
eBook Packages: MedicineMedicine (R0)