Advertisement

Receptor Tyrosine Kinases as Therapeutic Targets in Solid Tumors

  • Stacy L. Moulder
  • Carlos L. Arteaga
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

The introduction of nonspecific cytotoxic chemotherapeutic agents has provided palliation of symptoms, increased survival, and sometimes cure in patients with metastatic cancer. Unfortunately, patients with metastatic disease that are most likely to receive significant survival benefits from chemotherapy include those with less common malignancies, such as testis cancer and lymphoid neoplasms. In other more common malignancies, such as metastatic colon cancer or nonsmall-cell lung cancer (NSCLC), cytotoxic chemotherapy serves to palliate symptoms and has little or no role in prolonging life. Because of the nonspecific action of most current cytotoxic anticancer drugs, side effects such as bone marrow suppression, renal toxicity, and myocardial toxicity can often limit a patient’ s eligibility for and tolerance to therapy.

Keywords

Vascular Endothelial Growth Factor Epidermal Growth Factor Receptor Tyrosine Kinase Clin Oncol Metastatic Breast Cancer 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rowinsky EK. The pursuit of optimal outcomes in cancer therapy in a new age of rationally designed target-based anticancer agents. Drugs 2000; 60:1–14; discussion 41–42.Google Scholar
  2. 2.
    Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs 2000; 59: 753–767.PubMedCrossRefGoogle Scholar
  3. 3.
    Hunter T. Signaling–2000 and beyond. Cell 2000; 100: 113–127.PubMedCrossRefGoogle Scholar
  4. 4.
    Yarden Y, Sliwkowski MX. Untangling the ErbB network. Nature Rev 2001; 2: 127–137.CrossRefGoogle Scholar
  5. 5.
    Wells A. EGF receptor. Int J Biochem Cell Biol 1999; 31: 637–643.PubMedCrossRefGoogle Scholar
  6. 6.
    Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 1999; 13: 9–22.PubMedGoogle Scholar
  7. 7.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Yeo KT, Wang HH, Nagy JA, et al. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res 1993; 53: 2912–2918.PubMedGoogle Scholar
  9. 9.
    Fukumura D, Xavier R, Sugiura T, et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94: 715–725.PubMedCrossRefGoogle Scholar
  10. 10.
    Volm M, Koomagi R, Mattem J. Prognostic value of vascular endothelial growth factor and its receptor Flt-1 in squamous cell lung cancer. Int J Cancer 1997; 74: 64–68.PubMedCrossRefGoogle Scholar
  11. 11.
    Maeda K, Chung YS, Ogawa Y, et al. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 1996; 77: 858–863.PubMedCrossRefGoogle Scholar
  12. 12.
    Paley PJ, Staskus KA, Gebhard K, et al. Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 1997; 80: 98–106.PubMedCrossRefGoogle Scholar
  13. 13.
    Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 1997; 89: 139–147.PubMedCrossRefGoogle Scholar
  14. 14.
    Linderholm B, Tavelin B, Grankvist K, et al. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 1998; 16: 3121–3128.PubMedGoogle Scholar
  15. 15.
    Eppenberger U, Kueng W, Schlaeppi JM, et al. Markers of tumor angiogenesis and proteolysis independently define high-and low-risk subsets of node-negative breast cancer patients. J Clin Oncol 1998; 16: 3129–3136.PubMedGoogle Scholar
  16. 16.
    Klapper LN, Waterman H, Sela M, et al. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000; 60: 3384–3388.PubMedGoogle Scholar
  17. 17.
    Sliwkowski MX, Lofgren JA, Lewis GD, et al. Nonclinical studies addressing the mechanism of action of Trastuzumab (Herceptin). Semin Oncol 1999; 26 (Suppl 12): 60–70.PubMedGoogle Scholar
  18. 18.
    Viloria-Petit AM, Rak J, Hung M-C, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and In vivo. Am J Pathol 1997; 151: 1523–1530.Google Scholar
  19. 19.
    Clynes RA, Towers TL, Presta LG, et al. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nature Med 2000; 6: 443–446.PubMedCrossRefGoogle Scholar
  20. 20.
    Pietras RJ, Pegram MD, Finn RS, et al. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 1998; 17: 2235–2249.PubMedCrossRefGoogle Scholar
  21. 21.
    Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p 185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/ neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2659–2671.PubMedGoogle Scholar
  22. 22.
    Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-pl85HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996; 14: 737–744.PubMedGoogle Scholar
  23. 23.
    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.PubMedGoogle Scholar
  24. 24.
    Vogel C, Cobleigh MA, Tripathy D, et al. First-line, single-agent Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report. Eur J Cancer 2001; 37 (Suppl 1): 25–29.PubMedCrossRefGoogle Scholar
  25. 25.
    Mass RD, Sanders C, Charlene K, et al. The concordance between the clinical trials assay (CTA) and fluorescence in situ hybridization (FISH) in the Herceptin pivotal trials. Proc Am Soc Clin Oncol 2000; 19: 75 (abstr).Google Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    Burstein HJ, Kuter I, Richardson PG. Herceptin and Vinorelbine for HER-2 positive metastatic breast cancer: a phase II study. Proc Am Soc Clin Oncol 2000; 19: 102 (abstr).Google Scholar
  28. 28.
    Klijn JG, Berns PM, Schmitz PI, et al. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review of 5232 patients. Endocr Rev 1992; 13: 3–17.PubMedGoogle Scholar
  29. 29.
    Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.PubMedCrossRefGoogle Scholar
  30. 30.
    Fan Z, Lu Y, Wu X, et al. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. JBiol Chem 1994; 269:27, 595–27, 602.Google Scholar
  31. 31.
    Masui H, Kawamoto T, Sato JD, et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44: 1002–1007.PubMedGoogle Scholar
  32. 32.
    Wu X, Fan Z, Masui H, et al. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 1995; 95: 1897–1905.PubMedCrossRefGoogle Scholar
  33. 33.
    Divgi CR, Welt S, Kris M, et al. Phase I and imaging trial of indium 111-labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinomas. J Natl Cancer Inst 1991; 83: 97–194.PubMedCrossRefGoogle Scholar
  34. 34.
    Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1: 1311–1318.PubMedGoogle Scholar
  35. 35.
    Cohen RB, Falcey JW, Paulter VJ, et al. Safety profile of the monoclonal antibody (MoAb) IMC-C225, an anti-epidermal growth factor receptor (EGFr) used in the treatment of EGFr-positive tumors. Proc Am Soc Clin Oncol 2000; 19: 1862 (abstr).Google Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    Bonner JA, Ezekiel MP, Robert F, et al. Continued response following treatment with IMC-C225, an EGFr MoAb, combined with radiation therapy in advanced head and neck malignancies. Proc Am Soc Clin Oncol 2000; 19: 5F (abstr).Google Scholar
  38. 38.
    Strawn LM, Shawver LK. Tyrosine kinases in disease: Overview of kinase inhibitors as therapeutic agents and current drugs in clinical trials. Exp Opin Invest Drugs 1998; 7: 553–573.CrossRefGoogle Scholar
  39. 39.
    Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther 1999; 82: 207–218.PubMedCrossRefGoogle Scholar
  40. 40.
    Woodburn JR, Kendrew J, Fennell M, et al. ZD1839 (`Iressa’), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI): inhibition of c-fos mRNA, an intermediate marker of EGFR activation, correlates with tumor growth inhibition. Proc Am Assoc Cancer Res 2000; 41: 2552 (abstr).Google Scholar
  41. 41.
    Sirotnak FM, Zakowsky MF, Miller VA, et al. Potentiation of cytotoxic agents against human tumors in mice by ZD 1839 (Iressa) does not require high levels of expression of EGF receptors. Proc Am Assoc Cancer Res 2000; 41: 3076 (abstr).Google Scholar
  42. 42.
    Baselga J, Herbst R, LoRusso P, et al. Continuous administration of ZD 1839 (Iressa), a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in patients with five selected tumor types: evidence of activity and good tolerability. Proc Am Soc Clin Oncol 2000; 19: 177 (abstr).Google Scholar
  43. 43.
    Ferry K, Hammond L, Ranson M, et al. Intermittent oral ZD1839 (Iressa), a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), shows evidence of good tolerability and activity: final results from a phase I study. Proc Am Soc Clin Oncol 2000; 19: 3 (abstr).Google Scholar
  44. 44.
    Rao GS, Murray S, Ethier SP. Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor. Int J Radiat Oncol Biol Phys 2000; 48: 1519–1528.PubMedCrossRefGoogle Scholar
  45. 45.
    Moulder SL, Yakes M, Bianco R, et al. Small molecule EGF receptor tyrosine kinase inhibitor ZD 1839 (Iressa) inhibits HER2/neu (erbB-2) overexpressing breast tumor cells. Proc Am Soc Clin Oncol 2001; 20: 8 (abstr).Google Scholar
  46. 46.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.PubMedCrossRefGoogle Scholar
  47. 47.
    Schlaeppi JM, Wood JM. Targeting vascular endothelial growth factor (VEGF) for anti-tumor therapy, by anti-VEGF neutralizing monoclonal antibodies or by VEGF receptor tyrosine kinase inhibitors. Cancer Metastasis Rev 1999; 18: 473–481.PubMedCrossRefGoogle Scholar
  48. 48.
    Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983–985.PubMedCrossRefGoogle Scholar
  49. 49.
    Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306–1309.PubMedCrossRefGoogle Scholar
  50. 50.
    Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246: 1309–1312.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 1993; 362: 841–844.PubMedCrossRefGoogle Scholar
  52. 52.
    Millauer B, Longhi MP, Plate KH, et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 1996; 56: 1615–1620.PubMedGoogle Scholar
  53. 53.
    Witte L, Hicklin DJ, Zhu Z, et al. Monoclonal antibodies targeting the VEGF receptor-2 (Flk-1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev 1998; 17: 155–161.PubMedCrossRefGoogle Scholar
  54. 54.
    Fong TAT, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999; 59: 99–106.PubMedGoogle Scholar
  55. 55.
    Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of VEGF receptor tyrosine kinases, impairs VEGF-induced responses and tumor growth after oral administration. Cancer Res 2000; 60: 2178–2189.PubMedGoogle Scholar
  56. 56.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18: 4–25.PubMedCrossRefGoogle Scholar
  57. 57.
    Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia induced angiogenesis. Nature 1992; 359: 843–845.PubMedCrossRefGoogle Scholar
  58. 58.
    Boehm T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental cancer does not induce acquired resistance. Nature 1997; 390: 404–407.PubMedCrossRefGoogle Scholar
  59. 59.
    Stopeck A. Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Proc Am Soc Clin Oncol 2000; 19: 206 (abst).Google Scholar
  60. 60.
    Laird AD, Vajkoczy P, Shawver LK, et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000; 60: 4152–4160.PubMedGoogle Scholar
  61. 61.
    Rosen L, Hannah A, Rosen P, et al. Phase I dose-escalating trial of oral SU006668, a novel multiple receptor tyrosine kinase inhibitor in patients with selected advanced malignancies. Proc Am Soc Clin Oncol 2000; 19: 182 (abst).Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Stacy L. Moulder
  • Carlos L. Arteaga

There are no affiliations available

Personalised recommendations