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American Journal of Pharmacogenomics

, Volume 5, Issue 3, pp 173–190 | Cite as

Oncogenes as Novel Targets for Cancer Therapy (Part I)

Growth Factors and Protein Tyrosine Kinases
  • Zhuo Zhang
  • Mao Li
  • Elizabeth R. Rayburn
  • Donald L. Hill
  • Ruiwen Zhang
  • Hui WangEmail author
Targeted Therapeutics

Abstract

In the past 10 years, progress made in cancer biology, genetics, and biotechnology has led to a major transition in cancer drug design and development. There has been a change from an emphasis on non-specific, cytotoxic agents to specific, molecular-based therapeutics.

Mechanism-based therapy is designed to act on cellular and molecular targets that are causally involved in the formation, growth, and progression of human cancers. These agents, which may have greater selectivity for cancer versus normal cells, and which may produce better anti-tumor efficacy and lower host toxicity, can be small molecules, natural or engineered peptides, proteins, antibodies, or synthetic nucleic acids (e.g. antisense oligonucleotides, ribozymes, and siRNAs). Novel targets are identified and validated by state-of-the-art approaches, including high-throughput screening, combinatorial chemistry, and gene expression arrays, which increase the speed and efficiency of drug discovery and development. Examples of oncogene-based, molecular therapeutics that show promising clinical activity include trastuzumab (Herceptin®), imatinib (Gleevec®), and gefitinib (Iressa®).

However, the full potential of oncogenes as novel targets for cancer therapy has not been realized and many challenges remain, from the validation of novel targets, to the design of specific agents, to the evaluation of these agents in both preclinical and clinical settings. In maximizing the benefits of molecular therapeutics in monotherapy or combination therapy of cancer, it is necessary to have an understanding of the underlying molecular abnormalities and mechanisms involved.

This is the first part of a four-part review in which we discuss progress made in the last decade as it relates to the discovery of novel oncogenes and signal transduction pathways, in the context of their potential as targets for cancer therapy. This part delineates the latest discoveries about the potential use of growth factors and protein tyrosine kinases as targets for therapy. Later parts focus on intermediate signaling pathways, transcription factors, and proteins involved in cell cycle, DNA damage, and apoptotic pathways.

Keywords

Vascular Endothelial Growth Factor Tyrosine Kinase Imatinib Trastuzumab Hepatocyte Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This project was supported by grants from the National Institutes of Health/National Cancer Institute (R01 CA 80698 and R01 CA112029). Dr Wang was supported in part by funds from the Comprehensive Cancer Center, University of Alabama at Birmingham. Dr Z. Zhang was supported in part by a post-doctoral fellowship from the Department of Defense Prostate Cancer Research Program (grant number W81XWH-04-1-0845).

We realize that, due to the limitation of space, we could not cite all the excellent contributions published in this field, and we apologize for omission of many papers and reviews from our national and international colleagues.

The authors have no potential conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64: 235–48PubMedCrossRefGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70PubMedCrossRefGoogle Scholar
  3. 3.
    Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87: 159–70PubMedCrossRefGoogle Scholar
  4. 4.
    Hahn WC, Weinberg RA. Modeling the molecular circuitry of cancer. Nat Rev Cancer 2002; 2: 331–41PubMedCrossRefGoogle Scholar
  5. 5.
    Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–6PubMedCrossRefGoogle Scholar
  6. 6.
    Haupt S, Haupt Y. Manipulation of the tumor suppressor p53 for potentiating cancer therapy. Semin Cancer Biol 2003; 14: 244–52CrossRefGoogle Scholar
  7. 7.
    Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 2002; 1: 117–23PubMedCrossRefGoogle Scholar
  8. 8.
    Mass RD. The HER receptor family: a rich target for therapeutic development. Int J Radiat Oncol Biol Phys 2004; 58: 932–40PubMedCrossRefGoogle Scholar
  9. 9.
    Deveraux QL, Aza-Blanc P, Wagner KW, et al. Exposing oncogenic dependencies for cancer drug target discovery and validation using RNAi. Semin Cancer Biol. 2003; 13: 293–300PubMedCrossRefGoogle Scholar
  10. 10.
    Hermeking H. The MYC oncogene as a cancer drug target. Curr Cancer Drug Targets 2003; 3: 163–75PubMedCrossRefGoogle Scholar
  11. 11.
    Tolcher AW. Novel therapeutic molecular targets for prostate cancer: the mTOR signaling pathway and epidermal growth factor receptor. J Urol 2004; 171: S41–4PubMedCrossRefGoogle Scholar
  12. 12.
    Chang F, Steelman LS, Lee JT, et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003; 17: 1263–93PubMedCrossRefGoogle Scholar
  13. 13.
    Sun Y. Targeting e3 ubiquitin ligases for cancer therapy. Cancer Biol Ther 2003; 2: 23–9Google Scholar
  14. 14.
    Roberts AB, Sporn MB. Transforming growth factors. Cancer Surv 1985; 4: 683–705PubMedGoogle Scholar
  15. 15.
    Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 2003; 98: 257–65PubMedCrossRefGoogle Scholar
  16. 16.
    Roberts AB. Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 1998; 24: 111–9PubMedCrossRefGoogle Scholar
  17. 17.
    Cohen MM Jr. TGF beta/Smad signaling system and its pathologic correlates. Am J Med Genet. 2003; 116A: 1–10PubMedCrossRefGoogle Scholar
  18. 18.
    Tsukazaki T, Chiang TA, Davison AF, et al. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 1998; 95: 779–91PubMedCrossRefGoogle Scholar
  19. 19.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425: 577–84PubMedCrossRefGoogle Scholar
  20. 20.
    Chabot B, Stephenson DA, Chapman VM, et al. The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 1988; 335: 88–9PubMedCrossRefGoogle Scholar
  21. 21.
    Vinals F, Pouyssegur J. Transforming growth factor beta1 (TGF-β1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling. Mol Cell Biol 2001; 21: 7218–30PubMedCrossRefGoogle Scholar
  22. 22.
    Funaba M, Zimmerman CM, Mathews LS. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem 2002; 277: 41361–8PubMedCrossRefGoogle Scholar
  23. 23.
    Waite KA, Eng C. From developmental disorder to heritable cancer: it’s all in the BMP/TGF-beta family. Nat Rev Genet 2003; 4: 763–73PubMedCrossRefGoogle Scholar
  24. 24.
    Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A 2003; 100: 8621–3PubMedCrossRefGoogle Scholar
  25. 25.
    Akhurst RJ. TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest 2002; 109: 1533–6PubMedGoogle Scholar
  26. 26.
    Katakura Y, Nakata E, Tabira Y, et al. Decreased tumorigenicity in vivo when transforming growth factor beta treatment causes cancer cell senescence. Biosci Biotechnol Biochem 2003; 67: 815–21PubMedCrossRefGoogle Scholar
  27. 27.
    Sun L. Tumor-suppressive and promoting function of transforming growth factor beta. Front Biosci 2004; 9: 1925–35PubMedCrossRefGoogle Scholar
  28. 28.
    Chin D, Boyle GM, Parsons PG, et al. What is transforming growth factor-beta (TGF-beta)? Br J Plast Surg 2004; 7(3): 215–21CrossRefGoogle Scholar
  29. 29.
    Bhowmick NA, Chytil A, Plieth D, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303: 848–51PubMedCrossRefGoogle Scholar
  30. 30.
    Balmain A, Akhurst RJ. Cancer: dangerous liaisons. Nature 2004; 428: 271–2PubMedCrossRefGoogle Scholar
  31. 31.
    Benson JR. Role of transforming growth factor beta in breast carcinogenesis. Lancet Oncol 2004; 5: 229–39PubMedCrossRefGoogle Scholar
  32. 32.
    Tian F, DaCosta Byfield S, Parks WT, et al. Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2003; 63: 8284–92PubMedGoogle Scholar
  33. 33.
    Seton-Rogers SE, Lu Y, Hines LM, et al. Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A 2004; 101: 1257–62PubMedCrossRefGoogle Scholar
  34. 34.
    Siegel PM, Shu W, Cardiff RD, et al. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003; 100: 8430–5PubMedCrossRefGoogle Scholar
  35. 35.
    Muraoka RS, Koh Y, Roebuck LR, et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 2003; 23: 8691–703PubMedCrossRefGoogle Scholar
  36. 36.
    Deane NG, Lee H, Hamaamen J, et al. Enhanced tumor formation in cyclin D1 x transforming growth factor beta1 double transgenic mice with characterization by magnetic resonance imaging. Cancer Res 2004; 64: 1315–22PubMedCrossRefGoogle Scholar
  37. 37.
    Adler HL, McCurdy MA, Kattan MW, et al. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 1999; 161: 182–7PubMedCrossRefGoogle Scholar
  38. 38.
    Buck MB, Fritz P, Dippon J, et al. Prognostic significance of transforming growth factor beta receptor II in estrogen receptor-negative breast cancer patients. Clin Cancer Res 2004; 10: 491–8PubMedCrossRefGoogle Scholar
  39. 39.
    McEarchern JA, Kobie JJ, Mack V, et al. Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer 2001; 91: 76–82PubMedCrossRefGoogle Scholar
  40. 40.
    Lewis MP, Lygoe KA, Nystrom ML, et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 2004; 90: 822–32PubMedCrossRefGoogle Scholar
  41. 41.
    Kakonen SM, Selander KS, Chirgwin JM, et al. Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem 2002; 277: 24571–8PubMedCrossRefGoogle Scholar
  42. 42.
    Sellers RS, LeRoy BE, Blomme EA, et al. Effects of transforming growth factor-beta1 on parathyroid hormone-related protein mRNA expression and protein secretion in canine prostate epithelial, stromal, and carcinoma cells. Prostate 2004; 58: 366–73PubMedCrossRefGoogle Scholar
  43. 43.
    Philips N, McFadden K. Inhibition of transforming growth factor-beta and matrix metalloproteinases by estrogen and prolactin in breast cancer cells. Cancer Lett 2004; 206: 63–8PubMedCrossRefGoogle Scholar
  44. 44.
    Terabe M, Matsui S, Park JM, et al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 2003; 198: 1741–52PubMedCrossRefGoogle Scholar
  45. 45.
    Kobie JJ, Wu RS, Kurt RA, et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63: 1860–4PubMedGoogle Scholar
  46. 46.
    Kao J Y, Gong Y, Chen CM, et al. Tumor-derived TGF-beta reduces the efficacy of dendritic cell/tumor fusion vaccine. J Immunol 2003; 170: 3806–11PubMedGoogle Scholar
  47. 47.
    Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptorlike kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002; 62: 65–74PubMedCrossRefGoogle Scholar
  48. 48.
    Liang Y, Hou M, Kallab AM, et al. Induction of antiproliferation and apoptosis in estrogen receptor negative MDA-231 human breast cancer cells by mifepristone and 4-hydroxytamoxifen combination therapy: a role for TGFbeta1. Int J Oncol 2003; 23: 369–80PubMedGoogle Scholar
  49. 49.
    Lee BI, Park SH, Kim JW, et al. MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. Cancer Res 2001; 61: 931–4PubMedGoogle Scholar
  50. 50.
    Yang YA, Dukhanina O, Tang B, et al. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002; 109: 1607–15PubMedGoogle Scholar
  51. 51.
    Muraoka RS, Dumont N, Ritter CA, et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002; 109: 1551–9PubMedGoogle Scholar
  52. 52.
    Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 2003; 3: 531–6PubMedCrossRefGoogle Scholar
  53. 53.
    Ananth S, Knebelmann B, Gruning W, et al. Transforming growth factor beta1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res 1999; 59: 2210–6PubMedGoogle Scholar
  54. 54.
    Cambridge antibody technology [online]. Available from URL: http://www.cambridgeantibody.com [Accessed 2005 May 3]
  55. 55.
    Genzyme [online]. Available from URL: http://www.genzyme.com [Accessed 2005 May 3]
  56. 56.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669–76PubMedCrossRefGoogle Scholar
  57. 57.
    Hicklin DJ, Ellis LM. Role of the Vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23: 1–17Google Scholar
  58. 58.
    Shi W, Siemann D. Inhibition of renal cell carcinoma angiogenesis and growth by antisense oligonucleotides targeting vascular endothelial growth factor. Br J Cancer 2002; 87: 119–26PubMedCrossRefGoogle Scholar
  59. 59.
    Reinmuth N, Parikh AA, Ahmad SA, et al. Biology of angiogenesis in tumors of the gastrointestinal tract. Microsc Res Tech 2003; 60: 199–207PubMedCrossRefGoogle Scholar
  60. 60.
    Caponigro F, Basile M, Rosa VD, et al. New drugs in cancer therapy. Anticancer Drugs 2005; 16: 211–21PubMedCrossRefGoogle Scholar
  61. 61.
    Hadj TA. Bevacizumab for advanced colorectal cancer. Issues Emerg Health Technol 2004; 63: 1–4Google Scholar
  62. 62.
    Ignoffo RJ. Overview of bevacizumab: a new cancer therapeutic strategy targeting vascular endothelial growth factor. Am J Health Syst Pharm 2004; 61 (21 Suppl. 5): S21–6PubMedGoogle Scholar
  63. 63.
    Penland SK, Goldberg RM. Combining anti-VEGF approaches with oxaliplatin in advanced colorectal cancer. Clin Colorectal Cancer 2004; 4Suppl. 2: S74–80PubMedCrossRefGoogle Scholar
  64. 64.
    Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer 2004; 4Suppl. 2: S81–5PubMedCrossRefGoogle Scholar
  65. 65.
    Pavco PA, Bouhana KS, Gallegos AM, et al. Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. Clin Cancer Res 2000; 6: 2094–103PubMedGoogle Scholar
  66. 66.
    Venook A, Hurwitz H, Cunningham C, et al. Relationship of clinical outcome in metastatic colorectal carcinoma to levels of soluble VEGFR-1: results of a phase II trial of a ribozyme targeting the pre-mRNA of VEGFR-1 (Angiozyme) in combination with chemotherapy [abstract 1025]. Proc Am Soc Clin Oncol 2003; 22: 256Google Scholar
  67. 67.
    Riedel F, Gotte K, Li M, et al. Abrogation of VEGF expression in human head and neck squamous cell carcinoma decreases angiogenic activity in vitro and in vivo. Int J Oncol 2003; 23: 577–83PubMedGoogle Scholar
  68. 68.
    Lacombe J, Viazovkina E, Bernatchez P, et al. Antisense inhibition of Flk-1 by oligonucleotides composed of 2′-deoxy-2′-fluoro-beta-D-arabino- and 2′-deoxy-nucleosides. Can J Physiol Pharmacol 2002; 80: 951–61PubMedCrossRefGoogle Scholar
  69. 69.
    Wong RW, Guillaud L. The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine Growth Factor Rev 2004; 15: 147–56PubMedCrossRefGoogle Scholar
  70. 70.
    Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962; 237: 1555–62PubMedGoogle Scholar
  71. 71.
    Yamada M, Ikeuchi T, Hatanaka H. The neurotrophic action and signalling of epidermal growth factor. Prog Neurobiol 1997; 51: 19–37PubMedCrossRefGoogle Scholar
  72. 72.
    Wong RW, Chan SY. Semiquantitative immunoblots of membrane protein-epidermal growth factor. Mol Biotechnol 2000; 15: 65–7PubMedCrossRefGoogle Scholar
  73. 73.
    Savage CR Jr, Inagami T, Cohen S. The primary structure of epidermal growth factor. J Biol Chem 1972; 247: 7612–21PubMedGoogle Scholar
  74. 74.
    Wong RW, Kwan RW, Mak PH, et al. Overexpression of epidermal growth factor induced hypospermatogenesis in transgenic mice. J Biol Chem 2000; 275: 18297–301PubMedCrossRefGoogle Scholar
  75. 75.
    Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 1987; 56: 881–914PubMedCrossRefGoogle Scholar
  76. 76.
    Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37Suppl. 4: S3–8PubMedCrossRefGoogle Scholar
  77. 77.
    Marquardt H, Hunkapiller MW, Hood LE, et al. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 1984; 223: 1079–82PubMedCrossRefGoogle Scholar
  78. 78.
    Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res 2003; 284: 2–13PubMedCrossRefGoogle Scholar
  79. 79.
    Schlessinger J, Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron 1992; 9: 383–91PubMedCrossRefGoogle Scholar
  80. 80.
    Pawson T. Protein modules and signalling networks. Nature 1995; 373: 573–80PubMedCrossRefGoogle Scholar
  81. 81.
    van der Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994; 10: 251–337PubMedCrossRefGoogle Scholar
  82. 82.
    Bredt DS. Sorting out genes that regulate epithelial and neuronal polarity. Cell 1998; 94: 691–4PubMedCrossRefGoogle Scholar
  83. 83.
    Ullrich A, Coussens L, Hayflick JS, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 1984; 309: 418–25PubMedCrossRefGoogle Scholar
  84. 84.
    Korfee S, Gauler T, Hepp R, et al. New targeted treatments in lung cancer: overview of clinical trials. Lung Cancer 2004; 45Suppl. 2: S199–208PubMedCrossRefGoogle Scholar
  85. 85.
    Mosesson Y, Yarden Y. Oncogenic growth factor receptors: implications for signal transduction therapy. Semin Cancer Biol 2004; 14: 262–70PubMedCrossRefGoogle Scholar
  86. 86.
    Folprecht G, Kohne CH. The role of new agents in the treatment of colorectal cancer. Oncology 2004; 66: 1–17PubMedCrossRefGoogle Scholar
  87. 87.
    van der Poel HG. Smart drugs in prostate cancer. Eur Urol 2004; 45: 1–17PubMedCrossRefGoogle Scholar
  88. 88.
    Bonaccorsi L, Marchiani S, Muratori M, et al. Signaling mechanisms that mediate invasion in prostate cancer cells. Ann N Y Acad Sci 2004; 1028: 283–8PubMedCrossRefGoogle Scholar
  89. 89.
    Trojan L, Thomas D, Knoll T, et al. Expression of pro-angiogenic growth factors VEGF, EGF and bFGF and their topographical relation to neovascularisation in prostate cancer. Urol Res 2004; 32: 97–103PubMedCrossRefGoogle Scholar
  90. 90.
    Gregory CW, Fei X, Ponguta LA, et al. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem 2004; 279: 7119–30PubMedCrossRefGoogle Scholar
  91. 91.
    Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37Suppl. 4: S9–15PubMedCrossRefGoogle Scholar
  92. 92.
    Sartor CI. Biological modifiers as potential radiosensitizers: targeting the epidermal growth factor receptor family. Semin Oncol 2000; 27: 15–20; discussion 92-100PubMedGoogle Scholar
  93. 93.
    Shih A, Zhang S, Cao HJ, et al. Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. Mol Cancer Ther 2004; 3: 1355–64PubMedGoogle Scholar
  94. 94.
    Varela M, Ranuncolo SM, Morand A, et al. EGF-R and PDGF-R, but not bcl-2, overexpression predict overall survival in patients with low-grade astrocytomas. J Surg Oncol 2004; 86: 34–40PubMedCrossRefGoogle Scholar
  95. 95.
    Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995; 55: 5536–9PubMedGoogle Scholar
  96. 96.
    Lorimer IA. Mutant epidermal growth factor receptors as targets for cancer therapy. Curr Cancer Drug Targets 2002; 2: 91–102PubMedCrossRefGoogle Scholar
  97. 97.
    Lammering G, Hewit TH, Valerie K, et al. EGFRvIII-mediated radioresistance through a strong cytoprotective response. Oncogene 2003; 22: 5545–53PubMedCrossRefGoogle Scholar
  98. 98.
    Iqbal S, Lenz HJ. Integration of novel agents in the treatment of colorectal cancer. Cancer Chemother Pharmacol 2004; 54Suppl. 1: S32–9PubMedGoogle Scholar
  99. 99.
    Schiff BA, McMurphy AB, Jasser SA, et al. Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clin Cancer Res 2004; 10: 8594–602PubMedCrossRefGoogle Scholar
  100. 100.
    Kim SJ, Uehara H, Yazici S, et al. Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice. Cancer Res 2004; 64: 4201–8PubMedCrossRefGoogle Scholar
  101. 101.
    Sgambato A, Camerini A, Faraglia B, et al. Targeted inhibition of the epidermal growth factor receptor-tyrosine kinase by ZD1839 (‘Iressa’) induces cell-cycle arrest and inhibits proliferation in prostate cancer cells. J Cell Physiol 2004; 201: 97–105PubMedCrossRefGoogle Scholar
  102. 102.
    Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004; 58: 984–90PubMedCrossRefGoogle Scholar
  103. 103.
    Koizumi F, Kanzawa F, Ueda Y, et al. Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib (“Iressa”) and the DNA topoisomerase I inhibitor CPT-11 (irinotecan) in human colorectal cancer cells. Int J Cancer 2004; 108: 464–72PubMedCrossRefGoogle Scholar
  104. 104.
    Dancey JE, Freidlin B. Targeting epidermal growth factor receptor: are we missing the mark? Lancet 2003; 362: 62–4PubMedCrossRefGoogle Scholar
  105. 105.
    Padhy LC, Shih C, Cowing D, et al. Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 1982; 28: 865–71PubMedCrossRefGoogle Scholar
  106. 106.
    Yamamoto T, Ikawa S, Akiyama T, et al. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature 1986; 319: 230–4PubMedCrossRefGoogle Scholar
  107. 107.
    Nahta R, Esteva FJ. HER-2-targeted therapy: lessons learned and future directions. Clin Cancer Res 2003; 9: 5078–84PubMedGoogle Scholar
  108. 108.
    Ross JS, Fletcher JA, Linette GP, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003; 8: 307–25PubMedCrossRefGoogle Scholar
  109. 109.
    Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys 2004; 58: 903–13PubMedCrossRefGoogle Scholar
  110. 110.
    Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004; 44: 195–217PubMedCrossRefGoogle Scholar
  111. 111.
    Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the herceptin Fab. Nature 2003; 421: 756–60PubMedCrossRefGoogle Scholar
  112. 112.
    Garrett TP, McKern NM, Lou M, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003; 11: 495–505PubMedCrossRefGoogle Scholar
  113. 113.
    Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37: S3–8PubMedCrossRefGoogle Scholar
  114. 114.
    Menard S, Pupa SM, Campiglio M, et al. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003; 22: 6570–8PubMedCrossRefGoogle Scholar
  115. 115.
    Lee RJ, Albanese C, Fu M, et al. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 2000; 20: 672–83PubMedCrossRefGoogle Scholar
  116. 116.
    Zhou BP, Liao Y, Xia W, et al. Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 2001; 3: 245–52PubMedCrossRefGoogle Scholar
  117. 117.
    Zhou BP, Liao Y, Xia W, et al. HER-2/neu induces p53 ubiquitination via Aktmediated MDM2 phosphorylation. Nat Cell Biol 2001; 3: 973–82PubMedCrossRefGoogle Scholar
  118. 118.
    Foster CS, Gosden CM, Ke Y. HER2/neu expression in cancer: the pathologist as diagnostician or prophet? Hum Pathol 2003; 34: 635–8PubMedCrossRefGoogle Scholar
  119. 119.
    Garcia I, Vizoso F, Martin A, et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol 2003; 10: 234–41PubMedCrossRefGoogle Scholar
  120. 120.
    Zhou H, Randall RL, Brothman AR, et al. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol 2003; 25: 27–32PubMedCrossRefGoogle Scholar
  121. 121.
    Foster H, Knox S, Ganti AK, et al. HER-2/neu overexpression detected by immunohistochemistry in Soft Tissue Sarcomas. Am J Clin Oncol 2003; 26: 188–91PubMedCrossRefGoogle Scholar
  122. 122.
    Hogdall EV, Christensen L, Kjaer SK, et al. Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study. Cancer 2003; 98: 66–73PubMedCrossRefGoogle Scholar
  123. 123.
    van der Poel HG. Smart drugs in prostate cancer. Eur Urol 2004; 4: 1–17Google Scholar
  124. 124.
    Hirsch FR, Langer CJ. The role of HER2/neu expression and trastuzumab in non-small cell lung cancer. Semin Oncol 2004; 31 (1 Suppl. 1): 75–82PubMedCrossRefGoogle Scholar
  125. 125.
    Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER-2/ neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003; 95: 142–53PubMedCrossRefGoogle Scholar
  126. 126.
    Kim JA. Targeted therapies for the treatment of cancer. Am J Surg 2003; 186: 264–8PubMedCrossRefGoogle Scholar
  127. 127.
    Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21: 2889–95PubMedCrossRefGoogle Scholar
  128. 128.
    Vogel CL, Franco SX. Clinical experience with trastuzumab (herceptin). Breast J 2003; 9: 452–62PubMedCrossRefGoogle Scholar
  129. 129.
    Baselga J. Phase I and II clinical trials of trastuzumab. Ann Oncol 2001; 12Suppl. 1: S49–55PubMedCrossRefGoogle Scholar
  130. 130.
    Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–21PubMedCrossRefGoogle Scholar
  131. 131.
    Pegram MD, Konecny GE, O’Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96: 739–49PubMedCrossRefGoogle Scholar
  132. 132.
    Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004; 96: 759–69PubMedCrossRefGoogle Scholar
  133. 133.
    Burris H III, Yardley D, Jones S, et al. Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 2004; 22: 1621–9PubMedCrossRefGoogle Scholar
  134. 134.
    Azemar M, Djahansouzi S, Jager E, et al. Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2. Breast Cancer Res Treat 2003; 82: 155–64PubMedCrossRefGoogle Scholar
  135. 135.
    Dakappagari NK, Pyles J, Parihar R, et. al. A chimeric multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumor responses. J Immunol 2003; 170: 4242–53PubMedGoogle Scholar
  136. 136.
    Disis ML, Schiffman K, Guthrie K, et al. Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein-based vaccine. J Clin Oncol 2004; 22: 1916–25PubMedCrossRefGoogle Scholar
  137. 137.
    Wang SC, Hung MC. Transcriptional targeting of the HER-2/neu oncogene. Drugs Today (Barc) 2000; 36: 835–43Google Scholar
  138. 138.
    Tanabe K, Kim R, Inoue H, et al. Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs. Int J Oncol 2003; 22: 875–81PubMedGoogle Scholar
  139. 139.
    Barbacci EG, Pustilnik LR, Rossi AM, et al. The biological and biochemical effects of CP-654577, a selective erbB2 kinase inhibitor, on human breast cancer cells. Cancer Res 2003; 63: 4450–9PubMedGoogle Scholar
  140. 140.
    Hernes E, Fossa SD, Berner A, et al. Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Br J Cancer 2004; 90: 449–54PubMedCrossRefGoogle Scholar
  141. 141.
    Ratan HL, Gescher A, Steward WP, et al. ErbB receptors: possible therapeutic targets in prostate cancer? BJU Int 2003; 92: 890–5PubMedCrossRefGoogle Scholar
  142. 142.
    Rait AS, Pirollo KF, Ulick D, et al. HER-2-targeted antisense oligonucleotide results in sensitization of head and neck cancer cells to chemotherapeutic agents. Ann N Y Acad Sci 2003; 1002: 78–89PubMedCrossRefGoogle Scholar
  143. 143.
    Langer CJ, Stephenson P, Thor A, et al. Eastern Cooperative Oncology Group Study 2598. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role?: focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 2004; 22: 1180–7PubMedCrossRefGoogle Scholar
  144. 144.
    Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 1984; 311: 29–33PubMedCrossRefGoogle Scholar
  145. 145.
    Birchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 1998; 8: 404–10PubMedCrossRefGoogle Scholar
  146. 146.
    Matsumoto K, Nakamura T. NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci 2003; 94: 321–7PubMedCrossRefGoogle Scholar
  147. 147.
    Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem 2003; 88: 408–17PubMedCrossRefGoogle Scholar
  148. 148.
    Comoglio PM. Pathway specificity for Met signalling. Nat Cell Biol 2001; 3: E161–2PubMedCrossRefGoogle Scholar
  149. 149.
    Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915–25PubMedCrossRefGoogle Scholar
  150. 150.
    Potempa S, Ridley AJ. Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly. Mol Biol Cell 1998; 9: 2185–200PubMedGoogle Scholar
  151. 151.
    Royal I, Lamarche-Vane N, Lamorte L, et al. Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol Biol Cell 2000; 11: 1709–25PubMedGoogle Scholar
  152. 152.
    Yucel OT, Sungur A, Kaya S. c-Met overexpression in supraglottic laryngeal squamous cell carcinoma and its relation to lymph node metastases. Otolaryngol Head Neck Surg 2004; 130: 698–703PubMedCrossRefGoogle Scholar
  153. 153.
    Tsukinoki K, Yasuda M, Mori Y, et al. Hepatocyte growth factor and c-Met immunoreactivity are associated with metastasis in high grade salivary gland carcinoma. Oncol Rep 2004; 12: 1017–21PubMedGoogle Scholar
  154. 154.
    Trusolino L, Comoglio PM. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2002; 2: 289–300PubMedCrossRefGoogle Scholar
  155. 155.
    Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev 2003; 83: 337–76PubMedGoogle Scholar
  156. 156.
    Gallego MI, Bierie B, Hennighausen L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene 2003; 22: 8498–508PubMedCrossRefGoogle Scholar
  157. 157.
    Date K, Matsumoto K, Kuba K, et al. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene 1998; 17: 3045–54PubMedCrossRefGoogle Scholar
  158. 158.
    Nabeshima K, Inoue T, Shimao Y, et al. Front-cell-specific expression of membrane-type 1 matrix metalloproteinase and gelatinase A during cohort migration of colon carcinoma cells induced by hepatocyte growth factor/scatter factor. Cancer Res 2000; 60: 3364–9PubMedGoogle Scholar
  159. 159.
    Laterra J, Nam M, Rosen E, et al. Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab Invest 1997; 76: 565–77PubMedGoogle Scholar
  160. 160.
    Heideman DA, van Beusechem VW, Bloemena E, et al. Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. J Gene Med 2004; 6: 317–27PubMedCrossRefGoogle Scholar
  161. 161.
    Wen J, Matsumoto K, Taniura N, et al. Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor, suppresses liver metastasis and invasive growth of colon cancer in mice. Cancer Gene Ther 2004; 11: 419–30PubMedCrossRefGoogle Scholar
  162. 162.
    Kim SJ, Johnson M, Koterba K, et al. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin Cancer Res 2003; 9: 5161–70PubMedGoogle Scholar
  163. 163.
    Stabile LP, Lyker JS, Huang L, et al. Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy. Gene Ther 2004; 11: 325–35PubMedCrossRefGoogle Scholar
  164. 164.
    Christensen JG, Schreck R, Burrows J, et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003; 63: 7345–55PubMedGoogle Scholar
  165. 165.
    Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987; 6: 3341–51PubMedGoogle Scholar
  166. 166.
    d’Auriol L, Mattei MG, Andre C, et al. Localization of the human c-kit protooncogene on the q11-q12 region of chromosome 4. Hum Genet 1988; 78: 374–6PubMedCrossRefGoogle Scholar
  167. 167.
    Reilly JT. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev 2003; 17: 241–8PubMedCrossRefGoogle Scholar
  168. 168.
    Rossi P, Dolci S, Sette C, et al. Molecular mechanisms utilized by alternative c-kit gene products in the control of spermatogonial proliferation and sperm-mediated egg activation. Andrologia 2003; 35: 71–8PubMedCrossRefGoogle Scholar
  169. 169.
    Sattler M, Salgia R. Targeting KIT mutations: basic science to novel therapies. Leuk Res 2004; 28(Suppl.1): S11–20PubMedCrossRefGoogle Scholar
  170. 170.
    Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene 2002; 21: 3314–33PubMedCrossRefGoogle Scholar
  171. 171.
    Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 1988; 55: 185–92PubMedCrossRefGoogle Scholar
  172. 172.
    Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors. Cancer Genet Cytogenet 2002; 135: 1–22PubMedCrossRefGoogle Scholar
  173. 173.
    de Silva CM, Reid R. Gastrointestinal stromal tumors (GIST): C-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with Imatinib. Pathol Oncol Res 2003; 9: 13–9PubMedCrossRefGoogle Scholar
  174. 174.
    Micke P, Basrai M, Faldum A, et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003; 9: 188–94PubMedGoogle Scholar
  175. 175.
    Raspollini MR, Amunni G, Villanucci A, et al. c-KIT expression and correlation with chemotherapy resistance in ovarian carcinoma: an immunocytochemical study. Ann Oncol 2004; 15: 594–7PubMedCrossRefGoogle Scholar
  176. 176.
    Yasuoka R, Sakakura C, Shimomura K, et al. Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor. Dig Surg 2003; 20: 183–91PubMedCrossRefGoogle Scholar
  177. 177.
    Scobie JV, Acs G, Bandera CA, et al. C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance. Int J Gynecol Pathol 2003; 22: 149–55PubMedCrossRefGoogle Scholar
  178. 178.
    Dematteo RP, Heinrich MC, El-Rifai WM, et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002; 33: 466–77PubMedCrossRefGoogle Scholar
  179. 179.
    Gewirtz AM. Oligodeoxynucleotide-based therapeutics for human leukemias. Stem Cells 1993; 11: 96–103PubMedCrossRefGoogle Scholar
  180. 180.
    Yamanishi Y, Maeda H, Hiyama K, et al. Specific growth inhibition of small-cell lung cancer cells by adenovirus vector expressing antisense c-kit transcripts. Jpn J Cancer Res 1996; 87: 534–42PubMedCrossRefGoogle Scholar
  181. 181.
    Jones RH, Vasey PA. New directions in testicular cancer; molecular determinants of oncogenesis and treatment success. Eur J Cancer 2003; 39: 147–56PubMedCrossRefGoogle Scholar
  182. 182.
    Kindler T, Breitenbuecher F, Marx A, et al. Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia. Blood 2004; 103: 3644–54PubMedCrossRefGoogle Scholar
  183. 183.
    Zermati Y, De Sepulveda P, Feger F, et al. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene 2003; 22: 660–4PubMedCrossRefGoogle Scholar
  184. 184.
    Attoub S, Rivat C, Rodrigues S, et al. The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res 2002; 62: 4879–83PubMedGoogle Scholar
  185. 185.
    Camirand A, Pollak M. Co-targeting IGF-1R and c-kit: synergistic inhibition of proliferation and induction of apoptosis in H 209 small cell lung cancer cells. Br J Cancer 2004; 90: 1825–9PubMedGoogle Scholar
  186. 186.
    Matthews W, Jordan CT, Wiegand GW, et al. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 1991; 65: 1143–52PubMedCrossRefGoogle Scholar
  187. 187.
    Rosnet O, Marchetto S, deLapeyriere O, et al. Murine F1t3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 1991; 6: 1641–50PubMedGoogle Scholar
  188. 188.
    Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 1993; 82: 1110–9PubMedGoogle Scholar
  189. 189.
    Maroc N, Rottapel R, Rosnet O, et al. Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 1993; 8: 909–18PubMedGoogle Scholar
  190. 190.
    Sonneveld P, Pieters R. Immunophenotyping as a guide for targeted therapy. Best Pract Res Clin Haematol. 2003; 16: 629–44PubMedCrossRefGoogle Scholar
  191. 191.
    McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000; 95: 3489–97PubMedGoogle Scholar
  192. 192.
    Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995; 3: 147–61PubMedCrossRefGoogle Scholar
  193. 193.
    Lyman SD. Biology of flt3 ligand and receptor. Int J Hematol 1995; 62: 63–73PubMedCrossRefGoogle Scholar
  194. 194.
    Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia 2003; 17: 1738–52PubMedCrossRefGoogle Scholar
  195. 195.
    Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia 1996; 10: 588–99PubMedGoogle Scholar
  196. 196.
    Hawley TS, Fong AZ, Griesser H, et al. Leukemic predisposition of mice transplanted with gene-modified hematopoietic precursors expressing flt3 ligand. Blood. 1998; 92: 2003–11PubMedGoogle Scholar
  197. 197.
    Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004; 103: 1901–8PubMedCrossRefGoogle Scholar
  198. 198.
    Stirewalt DL, Meshinchi S, Radich JP. Molecular targets in acute myelogenous leukemia. Blood Rev 2003; 17: 15–23PubMedCrossRefGoogle Scholar
  199. 199.
    Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66PubMedCrossRefGoogle Scholar
  200. 200.
    Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–9PubMedCrossRefGoogle Scholar
  201. 201.
    Kottaridis PD, Gale RE, Linch DC. Flt3 mutations and leukemia. Br J Haematol 2003; 122: 523–38PubMedCrossRefGoogle Scholar
  202. 202.
    Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 2000; 96: 3907–14PubMedGoogle Scholar
  203. 203.
    Rombouts WJ, Blokland I, Lowenberg B, et al. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia 2000; 14: 675–83PubMedCrossRefGoogle Scholar
  204. 204.
    Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: 650–65PubMedCrossRefGoogle Scholar
  205. 205.
    Zheng R, Friedman AD, Levis M, et al. Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood 2004; 103: 1883–90PubMedCrossRefGoogle Scholar
  206. 206.
    Zwaan CM, Meshinchi S, Radich JP, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003; 102: 2387–94PubMedCrossRefGoogle Scholar
  207. 207.
    Beran M, Luthra R, Kantarjian H, et al. FLT3 mutation and response to intensive chemotherapy in young adult and elderly patients with normal karyotype. Leuk Res 2004; 28: 547–50PubMedCrossRefGoogle Scholar
  208. 208.
    Brown P, Small D. FLT3 inhibitors: a paradigm for the development of targeted therapeutics for paediatric cancer. Eur J Cancer 2004; 40: 707–21PubMedCrossRefGoogle Scholar
  209. 209.
    Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002; 99: 3885–91PubMedCrossRefGoogle Scholar
  210. 210.
    Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004; 103: 3669–76PubMedCrossRefGoogle Scholar
  211. 211.
    Stone RM, De Angelo J, Galinsky I, et al. PKC 412 FLT3 inhibitor therapy in AML: results of a phase II trial. Ann Hematol 2004; 83Suppl. 1: S89–90PubMedGoogle Scholar
  212. 212.
    Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003; 102: 2763–7PubMedCrossRefGoogle Scholar
  213. 213.
    O’Farrell AM, Foran JM, Fiedler W, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 2003; 9: 5465–76PubMedGoogle Scholar
  214. 214.
    Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A 2004; 101: 3130–5PubMedCrossRefGoogle Scholar
  215. 215.
    Goldman JM, Melo JV. Chronic myeloid leukemia: advances in biology and new approaches to treatment. N Engl J Med 2003; 349: 1451–64PubMedCrossRefGoogle Scholar
  216. 216.
    Nowell PC, Hungerford DA. A minute chromosome abnormality in human chronic granulocyte leukemia. Science 1960; 132: 1497Google Scholar
  217. 217.
    Kurzrock R, Kantarjian HM, Druker BJ, et al. Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003; 138: 819–30PubMedGoogle Scholar
  218. 218.
    Abelson HT, Rabstein LS. Lymphosarcoma: virus-induced thymic-independent disease in mice. Cancer Res 1970; 30: 2213–22PubMedGoogle Scholar
  219. 219.
    Deininger MW, Druker BJ. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev 2003; 55: 401–23PubMedCrossRefGoogle Scholar
  220. 220.
    Pluk H, Dorey K, Superti-Furga G. Autoinhibition of c-Abl. Cell 2002; 108: 247–59PubMedCrossRefGoogle Scholar
  221. 221.
    Stam K, Heisterkamp N, Reynolds FH, et al. Evidence that the phl gene encodes a 160,000-dalton phosphoprotein with associated kinase activity. Mol Cell Biol 1987; 7: 1955–60PubMedGoogle Scholar
  222. 222.
    Wetzler M, Talpaz M, Van Etten RA, et al. Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation. J Clin Invest 1993; 92: 1925–39PubMedCrossRefGoogle Scholar
  223. 223.
    Arlinghaus RB. The involvement of Bcr in leukemias with the Philadelphia chromosome. Crit Rev Oncog 1998; 9: 1–18PubMedCrossRefGoogle Scholar
  224. 224.
    Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–56PubMedGoogle Scholar
  225. 225.
    Van Etten RA. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res 2004; 28Suppl. 1: S21–8PubMedCrossRefGoogle Scholar
  226. 226.
    John AM, Thomas NS, Mufti GJ, et al. Targeted therapies in myeloid leukemia. Semin Cancer Biol 2004; 14: 41–62PubMedCrossRefGoogle Scholar
  227. 227.
    Kharas MG, Deane JA, Wong S, et al. Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 2004; 103: 4268–75PubMedCrossRefGoogle Scholar
  228. 228.
    Bedi A, Zehnbauer BA, Barber JP, et al. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 1994; 83: 2038–44PubMedGoogle Scholar
  229. 229.
    Cheng K, Kurzrock R, Qiu X, et al. Reduced focal adhesion kinase and paxillin phosphorylation in BCR-ABL-transfected cells. Cancer 2002; 95: 440–50PubMedCrossRefGoogle Scholar
  230. 230.
    Wong S, Witte ON. The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 2004; 22: 247–306PubMedCrossRefGoogle Scholar
  231. 231.
    Huettner CS, Zhang P, Van Etten RA, et al. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000; 24: 57–60PubMedCrossRefGoogle Scholar
  232. 232.
    O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004PubMedCrossRefGoogle Scholar
  233. 233.
    Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem 2004; 37: 618–35PubMedCrossRefGoogle Scholar
  234. 234.
    Lydon NB, Druker BJ. Lessons learned from the development of imatinib. Leuk Res 2004; 28 Suppl. 1: S29–38CrossRefGoogle Scholar
  235. 235.
    Hofmann WK, Komor M, Hoelzer D, et al. Mechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia. Leuk Lymphoma 2004; 45: 655–60PubMedCrossRefGoogle Scholar
  236. 236.
    Yoshida C, Melo JV. Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. Int J Hematol 2004; 79: 420–33PubMedCrossRefGoogle Scholar
  237. 237.
    Goldman JM. Chronic myeloid leukemia-still a few questions. Exp Hematol 2004; 32: 2–10PubMedCrossRefGoogle Scholar
  238. 238.
    Tauchi T, Ohyashiki K. Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk Res 2004; 28Suppl. 1: S39–45PubMedCrossRefGoogle Scholar
  239. 239.
    Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004; 103: 2873–8PubMedCrossRefGoogle Scholar
  240. 240.
    Gorre ME, Ellwood-Yen K, Chiosis G, et al. 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: 3041–4PubMedCrossRefGoogle Scholar
  241. 241.
    Li MJ, McMahon R, Snyder DS, et al. Specific killing of Ph+ chronic myeloid leukemia cells by a lentiviral vector-delivered anti-bcr/abl small hairpin RNA. Oligonucleotides 2003; 13: 401–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Zhuo Zhang
    • 1
  • Mao Li
    • 1
  • Elizabeth R. Rayburn
    • 1
  • Donald L. Hill
    • 1
    • 2
  • Ruiwen Zhang
    • 1
    • 2
    • 3
  • Hui Wang
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacology and Toxicology, and Division of Clinical PharmacologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Comprehensive Cancer CenterUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Gene Therapy CenterUniversity of Alabama at BirminghamBirminghamUSA

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