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Evolving molecular-based targeted therapy for cancer An exciting field

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Comprehensive Therapy

Abstract

The development of molecular biology tools has led to the identification of numerous therapeutic targets in cancer cells. In this article, we discuss the rational and clinical data supporting the use of agents that selectively target epidermal and vascular endothelial growth factors in selected cancers.

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References

  1. Rutman R, Cantarow A, Paschkis K. Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil-2-C14 by preneoplastic rat liver and rat hepatoma. Cancer Res 1954;14:119–123.

    PubMed  CAS  Google Scholar 

  2. Heidelberger C, Chaudhuri N, Danneberg P, et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957;179:663–666.

    Article  PubMed  CAS  Google Scholar 

  3. Robinson DR, Wu YM, and Lin SF: The protein tyrosine kinase family of the human genome. Oncogene 2000:19:5548–5557.

    Article  PubMed  CAS  Google Scholar 

  4. Gschwind A, Fischer OM, and Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004;4:361–370.

    Article  PubMed  CAS  Google Scholar 

  5. Krause DS, and Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005:353:172–187.

    Article  PubMed  CAS  Google Scholar 

  6. Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  7. Chan TO, Rittenhouse SE, and Tsichlis PN: AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1996;68:965–1014.

    Article  Google Scholar 

  8. Ozanne B, Richards CS, Hendler F, et al. Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J Pathol 1986:149:9–14.

    Article  PubMed  CAS  Google Scholar 

  9. Mendelsohn J: Blockade of receptors for growth factors: an anticancer therapy—the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res 2000;6:747–753.

    PubMed  CAS  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    PubMed  CAS  Google Scholar 

  12. Pomerantz RG and Grandis JR. The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. Semin Oncol 2004;31:734–743.

    Article  PubMed  CAS  Google Scholar 

  13. Baselga J, Trigo JM, Bourthis J, et al. Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum based agent. Proc Am Soc Clin Oncol 2002;21:226.

    Google Scholar 

  14. 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;23:618.

    Google Scholar 

  15. Lynch TJ, Lilenbaum R, Bonomi P, et al. A phase II trial of cetuximab as therapy for recurrent non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004;22:637.

    Google Scholar 

  16. Reynolds NA and Wagstaff AJ: Cetuximab: in the treatment of metastatic colorectal cancer. Drugs 2004;64:109–118.

    Article  PubMed  CAS  Google Scholar 

  17. Hecht JR, Patnaik A, Malik I, et al. ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis. Proc Am Soc Clin Oncol 2004: 23:248.

    Google Scholar 

  18. Salazar R, Tabernero J, Rojo F, et al. Dose-dependent inhibition of the EGFR and signaling pathways with the anti-EGFR monoclonal antibody (MAb) EMD 72000 administered every three weeks (q3w). A phase I pharmacokinetic/pharmacodynamic (PK/PD) study to define the optimal biological dose (OBD). Proc Am Soc Clin Oncol 2004;23:127.

    Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–2158.

    Article  PubMed  CAS  Google Scholar 

  22. Massarelli E, Andre F, Liu DD, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55–61.

    Article  PubMed  CAS  Google Scholar 

  23. van Zandwijk N: Tolerability of gefitinib in patients receiving treatment in everyday clinical practice. Br J Cancer 2003;89 Suppl 2:S9–14.

    Article  PubMed  CAS  Google Scholar 

  24. Thatcher N, Chang A, Parikh P, et al. Results of a Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proceedings of the 96th Annual Meeting of the American Association for Cancer Research, 2005.

  25. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22:3238–3247.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004;22:777–784.

    Article  PubMed  CAS  Google Scholar 

  28. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004;22:785–794.

    Article  PubMed  CAS  Google Scholar 

  29. 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 2004:23:617.

    Google Scholar 

  30. Herbst RS, Prager D, Hermann R, et al. TRIBUTE-A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2004;23:617.

    Google Scholar 

  31. Miller VA, Herbst R, Prager D, et al. Long survival of never smoking non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib HCl (OSI-774) and chemotherapy: Sub-group analysis of TRIBUTE. Proc Am Soc Clin Oncol 2004;23:628.

    Google Scholar 

  32. Lim ST, Wong EH, Chuah KL, et al. Gefitinib is more effective in never-smokers with non-small-cell lung cancer: experience among Asian patients. Br J Cancer 2005;93:23–28.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  CAS  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–13311.

    Article  PubMed  CAS  Google Scholar 

  36. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.

    Article  PubMed  CAS  Google Scholar 

  37. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–1987.

    Article  PubMed  CAS  Google Scholar 

  38. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77–85.

    Article  PubMed  CAS  Google Scholar 

  39. Cohen E, Haraf D, Stenson K, et al. Integration of gefitinib (G), into a concurrent chemoradiation (CRT) regimen followed by G adjuvant therapy in patients with locally advanced head and neck cancer (HNC)—a Phase II Trial. Proc Am Soc Clin Oncol 2005;23:501.

    Google Scholar 

  40. Carneiro B, Brand R, Fine E, et al. Phase I trial of fixed dose rate infusion (FDRI) gemcitabine (GEM) with gefitinib in patients with advanced pancreatic carcinoma. Proc Am Soc Clin Oncol 2005;23:227.

    Google Scholar 

  41. Moore M, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. Proc Am Soc Clin Oncol 2005;23:1.

    Google Scholar 

  42. Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–1186.

    Article  PubMed  CAS  Google Scholar 

  43. Zondor SD and Medina PJ: Bevacizumab: an angiogenesis inhibitor with efficacy in colorectal and other malignancies. Ann Pharmacother 2004;38:1258–1264.

    Article  PubMed  CAS  Google Scholar 

  44. Thorpe PE, Chaplin DJ, and Blakey DC: The first international conference on vascular targeting: meeting overview. Cancer Res 2003;63:1144–1147.

    PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Gerber HP, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002;417:954–958.

    Article  PubMed  CAS  Google Scholar 

  47. Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature 2000;407:249–257.

    Article  PubMed  CAS  Google Scholar 

  48. Ferrara N: Role of vascular endothelial growth factor, in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 2001;280:C1358-C1366.

    PubMed  CAS  Google Scholar 

  49. Gupta K, Gupta P, Wild R, et al. Binding and displacement of vascular endothelial growth factor (VEGF) by thrombospondin: effect on human microvascular endothelial cell proliferation and angiogenesis. Angiogenesis 1999;3:147–158.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. Miller KD, Wang M, Gralow J, et al. E2100. A randomized phase III trial of paclitaxel versus paclitaxel plus bezacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc Am Soc Clin Oncol 2005;23. (Late-breaking session).

  53. 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.

    Article  PubMed  CAS  Google Scholar 

  54. 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.

    Article  PubMed  CAS  Google Scholar 

  55. Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002;21:37.

    Google Scholar 

  56. Keates S, Sougioultzis S, Keates AC et al. cag+Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol. Chem 2001;276:48127–48134.

    Article  PubMed  CAS  Google Scholar 

  57. Lemjabbar H and Basbaum C: Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med 2002;8:41–46.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Janardan Khandekar.

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The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article. The authors do not discuss the use of off-label products, which includes unlabeled, unapproved, or investigative products or devices.

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Carneiro, B., Hsiao, K. & Khandekar, J. Evolving molecular-based targeted therapy for cancer An exciting field . Compr Ther 31, 299–305 (2005). https://doi.org/10.1385/COMP:31:4:299

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  • DOI: https://doi.org/10.1385/COMP:31:4:299

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