Skip to main content
SpringerLink
Log in

Targeted Therapies in Cancer

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Recent advances in understanding the biologic mechanisms underlying cancer development have driven the design of new therapeutic approaches, termed ‘targeted therapies’, that selectively interfere with molecules or pathways involved in tumor growth and progression. Inactivation of growth factors and their receptors on tumor cells as well as the inhibition of oncogenic tyrosine kinase pathways and the inhibition of molecules that control specific functions in cancer cells constitute the main rational bases of new cancer treatments tailored for individual patients. Small-molecule inhibitors and monoclonal antibodies are major components of these targeted approaches for a number of human malignancies. As the studies of the biomolecular features of cancer progress, new exciting strategies have arisen, such as targeting cancer stem cells that drive tumor relapses or the selective induction of apoptosis in malignant cells. This article primarily focuses on the biologic bases of the new cancer drugs and summarizes their mechanisms of action, the clinical evidence of their anti-cancer effectiveness as well as the rationale for their use in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Infield GB. Disaster at Bari. New York: Mcmillan, 1971

    Google Scholar 

  2. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8(10): 755–68

    Article  PubMed  CAS  Google Scholar 

  3. FDA-approved drugs. Boston (MA): CenterWatch, 2007 [online]. Available from URL: http://www.centerwatch.com/drug-information/fda-approvals [Accessed 2010 Jan 22]

  4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57–70

    Article  PubMed  CAS  Google Scholar 

  5. Hochhaus A. Imatinib mesylate (Glivec, Gleevec) in the treatment of CML and GIST. Ann Hematol 2004; 83 Suppl. 1: S65–6

    PubMed  Google Scholar 

  6. Soverini S, Martinelli G, Iacobucci I, et al. Imatinib mesylate for the treatment of chronic myeloid leukemia. Expert Rev Anticancer Ther 2008; 8(6): 853–64

    Article  PubMed  CAS  Google Scholar 

  7. Bardelli A, Parsons DW, Silliman N, et al. Mutational analysis of the tyrosine kinome in colorectal cancers [letter]. Science 2003; 300(5621): 949

    Article  PubMed  CAS  Google Scholar 

  8. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351(9114): 1451–67

    Article  Google Scholar 

  9. Grandis JR, Sok JC. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther 2004; 102(1): 37–46

    Article  PubMed  CAS  Google Scholar 

  10. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002; 7Suppl. 4: 2–8

    Article  PubMed  CAS  Google Scholar 

  11. Menard S, Pupa SM, Campiglio M, et al. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003; 22(42): 6570–8

    Article  PubMed  CAS  Google Scholar 

  12. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358(11): 1160–74

    Article  PubMed  CAS  Google Scholar 

  13. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235(4785): 177–82

    Article  PubMed  CAS  Google Scholar 

  14. Shields JM, Pruitt K, McFall A, et al. Understanding Ras: ‘it ain’t over ‘til it’s over’’. Trends Cell Biol 2000; 10(4): 147–54

    Article  PubMed  CAS  Google Scholar 

  15. Kato K, Cox AD, Hisaka MM, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A 1992; 89(14): 6403–7

    Article  PubMed  CAS  Google Scholar 

  16. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005; 23(5): 1028–43

    Article  PubMed  CAS  Google Scholar 

  17. Ng R, Chen EX. Sorafenib (BAY 43-9006): review of clinical development. Curr Clin Pharmacol 2006; 1(3): 223–8

    Article  PubMed  CAS  Google Scholar 

  18. Roccaro AM, Vacca A, Ribatti D. Bortezomib in the treatment of cancer. Recent Pat Anticancer Drug Discov 2006; 1(3): 397–403

    Article  PubMed  CAS  Google Scholar 

  19. Ribatti D, Nico B, Crivellato E, et al. The history of the angiogenic switch concept. Leukemia 2007; 21(1): 44–52

    Article  PubMed  CAS  Google Scholar 

  20. Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med 2003; 3(7): 643–51

    Article  PubMed  CAS  Google Scholar 

  21. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9(6): 669–76

    Article  PubMed  CAS  Google Scholar 

  22. Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the anti-tumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61(13): 5090–101

    PubMed  CAS  Google Scholar 

  23. Ribatti D, Vacca A. Novel therapeutic approaches targeting vascular endothelial growth factor and its receptors in haematological malignancies. Curr Cancer Drug Targets 2005; 5(8): 573–8

    Article  PubMed  CAS  Google Scholar 

  24. Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res 2004; 10(12Pt2): 4258s–62s

    Article  PubMed  CAS  Google Scholar 

  25. Bhowmick NA, Chytil A, Plieth D, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004; 303(5659): 848–51

    Article  PubMed  CAS  Google Scholar 

  26. Jones E, Pu H, Kyprianou N. Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression. Expert Opin Ther Targets 2009; 13(2): 227–34

    Article  PubMed  CAS  Google Scholar 

  27. Park CH, Bergsagel DE, McCulloch EA. Mouse myeloma tumor stem cells: a primary cell culture assay. J Natl Cancer Inst 1971; 46(2): 411–22

    PubMed  CAS  Google Scholar 

  28. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3(7): 730–7

    Article  PubMed  CAS  Google Scholar 

  29. Galderisi U, Cipollaro M, Giordano A. Stem cells and brain cancer. Cell Death Differ 2006; 13(1): 5–11

    Article  PubMed  CAS  Google Scholar 

  30. Pfeiffer MJ, Schalken JA. Stem Cell Characteristics in Prostate Cancer Cell Lines. Eur Urol. Epub 2009 Jan 19

  31. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009; 69(4): 1302–13

    Article  PubMed  CAS  Google Scholar 

  32. Groszer M, Erickson R, Scripture-Adams DD, et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 2001; 294(5549): 2186–9

    Article  PubMed  CAS  Google Scholar 

  33. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell 2008; 15(6): 801–12

    Article  PubMed  CAS  Google Scholar 

  34. Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res 2007; 13(14): 4042–5

    Article  PubMed  CAS  Google Scholar 

  35. Massard C, Deutsch E, Soria JC. Tumour stem cell-targeted treatment: elimination or differentiation. Ann Oncol 2006; 17(11): 1620–4

    Article  PubMed  CAS  Google Scholar 

  36. Adams GP, Schier R, McCall AM, et al. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res 2001; 61(12): 4750–5

    PubMed  CAS  Google Scholar 

  37. D’Alessandro AM, Pirsch JD, Stratta RJ, et al. OKT3 salvage therapy in a quadruple immunosuppressive protocol in cadaveric renal transplantation. Transplantation 1989; 47(2): 297–300

    Article  PubMed  Google Scholar 

  38. Qu Z, Griffiths GL, Wegener WA, et al. Development of humanized antibodies as cancer therapeutics. Methods 2005; 36(1): 84–95

    Article  PubMed  CAS  Google Scholar 

  39. Moroney S, Pluckthun A. Modern antibody technology: the impact on drug development. In: Knaeblein J, editor. Modern biopharmaceuticals. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2005: 1147–86

    Chapter  Google Scholar 

  40. Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001; 1(2): 118–29

    Article  PubMed  CAS  Google Scholar 

  41. Zhang N, Khawli LA, Hu P, et al. Generation of rituximab polymer may cause hyper-cross-linking-induced apoptosis in non-Hodgkin’s lymphomas. Clin Cancer Res 2005; 11(16): 5971–80

    Article  PubMed  CAS  Google Scholar 

  42. Bianco R, Daniele G, Ciardiello F, et al. Monoclonal antibodies targeting the epidermal growth factor receptor. Curr Drug Targets 2005; 6(3): 275–87

    Article  PubMed  CAS  Google Scholar 

  43. Emens LA. Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer. Am J Ther 2005; 12(3): 243–53

    PubMed  Google Scholar 

  44. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16(8): 2825–33

    PubMed  CAS  Google Scholar 

  45. Coiffier B. First-line treatment of follicular lymphoma in the era of monoclonal antibodies. Clin Adv Hematol Oncol 2005; 3(6): 484–91, 505

    PubMed  Google Scholar 

  46. Quintas-Cardama A, O’Brien S. Targeted therapy for chronic lymphocytic leukemia. Target Oncol 2009; 4(1): 11–21

    Article  PubMed  Google Scholar 

  47. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006; 24(18): 2786–92

    Article  PubMed  CAS  Google Scholar 

  48. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1673–84

    Article  PubMed  CAS  Google Scholar 

  49. 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(4): 337–45

    Article  PubMed  CAS  Google Scholar 

  50. Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. 2007 ASCO Annual Meeting Proceedings Part I, 2007. J Clin Oncol; 25Suppl. 18S: 4000

    Google Scholar 

  51. de Gramont A, Van Cutsem E. Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. Oncology 2005; 69Suppl. 3: 46–56

    Article  PubMed  CAS  Google Scholar 

  52. D’Adamo DR, Anderson SE, Albritton K, et al. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol 2005; 23(28): 7135–42

    Article  PubMed  CAS  Google Scholar 

  53. Bruns I, Fox F, Reinecke P, et al. Complete remission in a patient with relapsed angioimmunoblastic T-cell lymphoma following treatment with bevacizumab. Leukemia 2005; 19(11): 1993–5

    Article  PubMed  CAS  Google Scholar 

  54. Czuczman MS. CHOP plus rituximab chemoimmunotherapy of indolent B-cell lymphoma. Semin Oncol 1999; 26(5 Suppl. 14): 88–96

    PubMed  CAS  Google Scholar 

  55. Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005; 11 (2 Pt 1): 795–805

    PubMed  CAS  Google Scholar 

  56. Goldenberg DM, Horowitz JA, Sharkey RM, et al. Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody. J Clin Oncol 1991; 9(4): 548–64

    PubMed  CAS  Google Scholar 

  57. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 2005; 23(9): 1137–46

    Article  PubMed  CAS  Google Scholar 

  58. Frankel AE, Kreitman RJ, Sausville EA. Targeted toxins. Clin Cancer Res 2000; 6(2): 326–34

    PubMed  CAS  Google Scholar 

  59. Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2002; 20(10): 2453–63

    Article  PubMed  CAS  Google Scholar 

  60. Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 2005; 23(30): 7565–73

    Article  PubMed  CAS  Google Scholar 

  61. Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005; 352(5): 441–9

    Article  PubMed  CAS  Google Scholar 

  62. 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 2003; 101(1): 97–100

    Article  PubMed  CAS  Google Scholar 

  63. 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(7): 472–80

    Article  PubMed  CAS  Google Scholar 

  64. Gum RJ, McLaughlin MM, Kumar S, et al. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket. J Biol Chem 1998; 273(25): 15605–10

    Article  PubMed  CAS  Google Scholar 

  65. Wang Z, Canagarajah BJ, Boehm JC, et al. Structural basis of inhibitor selectivity in MAP kinases. Structure 1998; 6(9): 1117–28

    Article  PubMed  CAS  Google Scholar 

  66. 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(1): 16–24

    Article  PubMed  CAS  Google Scholar 

  67. Motzer RJ, Michaelson MD, Rosenberg J, et al. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007; 178(5): 1883–7

    Article  PubMed  CAS  Google Scholar 

  68. Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8(4): 303–6

    Article  PubMed  CAS  Google Scholar 

  69. Johnson JR, Cohen M, Sridhara R, et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 2005; 11(18): 6414–21

    Article  PubMed  CAS  Google Scholar 

  70. Nelson MH, Dolder CR. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother 2006; 40(2): 261–9

    Article  PubMed  CAS  Google Scholar 

  71. 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(11): 1427–38

    PubMed  CAS  Google Scholar 

  72. 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(5531): 876–80

    Article  PubMed  CAS  Google Scholar 

  73. Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004; 127(1): 294–9

    Article  PubMed  CAS  Google Scholar 

  74. 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(8): 786–92

    Article  PubMed  CAS  Google Scholar 

  75. Ohren JF, Chen H, Pavlovsky A, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 2004; 11(12): 1192–7

    Article  PubMed  CAS  Google Scholar 

  76. Adrian FJ, Ding Q, Sim T, et al. Allosteric inhibitors of Bcr-abl-dependentcell proliferation. Nat Chem Biol 2006; 2(2): 95–102

    Article  PubMed  CAS  Google Scholar 

  77. Bapat SA, Mali AM, Koppikar CB, et al. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 2005; 65(8): 3025–9

    PubMed  CAS  Google Scholar 

  78. Vlashi E, Kim K, Lagadec C, et al. In vivo imaging, tracking, and targeting of cancer stem cells. J Natl Cancer Inst 2009; 101(5): 350–9

    Article  PubMed  CAS  Google Scholar 

  79. Al-Hajj M, Becker MW, Wicha M, et al. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 2004; 14(1): 43–7

    Article  PubMed  CAS  Google Scholar 

  80. Sakariassen PO, Immervoll H, Chekenya M. Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 2007; 9(11): 882–92

    Article  PubMed  CAS  Google Scholar 

  81. Lou H, Dean M. Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene 2007; 26(9): 1357–60

    Article  PubMed  CAS  Google Scholar 

  82. Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15(9): 494–501

    Article  PubMed  CAS  Google Scholar 

  83. Gibbs CP, Kukekov VG, Reith JD, et al. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 2005; 7(11): 967–76

    Article  PubMed  CAS  Google Scholar 

  84. Harley CB. Telomerase and cancer therapeutics. Nat Rev Cancer 2008; 8(3): 167–79

    Article  PubMed  CAS  Google Scholar 

  85. Jimeno A, Feldmann G, Suarez-Gauthier A, et al. A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 2009; 8(2): 310–4

    Article  PubMed  CAS  Google Scholar 

  86. Eichenmuller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology 2009; 49(2): 482–90

    Article  PubMed  CAS  Google Scholar 

  87. Warzecha J, Bonke L, Koehl U, et al. The hedgehog inhibitor cyclopamine induces apoptosis in leukemic cells in vitro. Leuk Lymphoma 2008; 49(12): 2383–6

    Article  PubMed  CAS  Google Scholar 

  88. Berman DM, Karhadkar SS, Hallahan AR, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 2002; 297(5586): 1559–61

    Article  PubMed  CAS  Google Scholar 

  89. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004; 432(7015): 324–31

    Article  PubMed  CAS  Google Scholar 

  90. Bin Hafeez B, Adhami VM, Asim M, et al. Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin Cancer Res 2009; 15(2): 452–9

    Article  CAS  Google Scholar 

  91. Tang C, Ang BT, Pervaiz S. Cancer stem cell: target for anti-cancer therapy. Faseb J 2007; 21(14): 3777–85

    Article  PubMed  CAS  Google Scholar 

  92. Yang ZJ, Wechsler-Reya RJ. Hit ‘em where they live: targeting the cancer stem cell niche. Cancer Cell 2007; 11(1): 3–5

    Article  PubMed  CAS  Google Scholar 

  93. Gulbins E, Jekle A, Ferlinz K, et al. Physiology of apoptosis. Am J Physiol Renal Physiol 2000; 279(4): F605–15

    PubMed  CAS  Google Scholar 

  94. Bouralexis S, Findlay DM, Evdokiou A. Death to the bad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 2005; 10(1): 35–51

    Article  PubMed  CAS  Google Scholar 

  95. Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 2004;4(4): 333–9

    Article  PubMed  CAS  Google Scholar 

  96. Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001; 98(3): 795–804

    Article  PubMed  CAS  Google Scholar 

  97. Daniel D, Yang B, Lawrence DA, et al. Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts. Blood 2007; 110(12): 4037–46

    Article  PubMed  CAS  Google Scholar 

  98. Labrinidis A, Diamond P, Martin S, et al. ApoL/TRAIL inhibits tumor growth and bone desrtuction in a murin model of multiple myeloma. Clin Cancer Res 2009; 15(6): 1998–2009

    Article  PubMed  CAS  Google Scholar 

  99. Mitsiades N, Mitsiades CS, Poulaki V, et al. Concepts in the use of TRAIL/Apo2L: an emerging biotherapy for myeloma and other neoplasias. Expert Opin Investig Drugs 2001; 10(8): 1521–30

    Article  PubMed  CAS  Google Scholar 

  100. Balsas P, Lopez-Royuela N, Galan-Malo P, et al. Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis. Biochem Pharmacol 2009; 77(5): 804–12

    Article  PubMed  CAS  Google Scholar 

  101. El-Zawahry A, McKillop J, Voelkel-Johnson C. Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts. BMC Cancer 2005; 5: 2–11

    Article  PubMed  CAS  Google Scholar 

  102. Frese S, Brunner T, Gugger M, et al. Enhancement of Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in non-small cell lung cancer cell lines by chemotherapeutic agents without correlation to the expression level of cellular protease caspase-8 inhibitory protein. J Thorac Cardiovasc Surg 2002; 123(1): 168–74

    Article  PubMed  CAS  Google Scholar 

  103. Herbst RS, Mendolson DS, Ebbinghaus S, et al. A phase I safety and pharmacokinetic study in patients with advanced cancer treated with recombinant Apo2L/TRAIL, an apoptosis-inducing protein [abstract]. J Clin Oncol 2006; 24: 3013

    Article  Google Scholar 

  104. Yee L, Fanale M, Dimick K, et al. Results of a phase Ib study of recombinant human Apo2L/TRAIL with rituximab in patients with relapsed, low-grade NHL [abstract]. Ann Oncol 2008; 19Suppl. 4: iv161

    Google Scholar 

  105. Soria J, Smit EF, Khayat D, et al. Phase Ib study of recombinant human (rh)Apo2L/TRAIL in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients (pts) with advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2008; 26: 3539

    Google Scholar 

  106. Plummer R, Attard G, Pacey S, et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 2007; 13(20): 6187–94

    Article  PubMed  CAS  Google Scholar 

  107. Pukac L, Kanakaraj P, Humphreys R, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 2005; 92(8): 1430–41

    Article  PubMed  CAS  Google Scholar 

  108. Tolcher AW, Mita M, Meropol NJ, et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007; 25(11): 1390–5

    Article  PubMed  CAS  Google Scholar 

  109. Zhang L, Zhang X, Barrisford GW, et al. Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Lett 2007; 251(1): 146–57

    Article  PubMed  CAS  Google Scholar 

  110. Kanzler S, Trarbach T, Heinemann V, et al. Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC) [abstract no. 630]. 13th European Cancer Conference; 2005 Oct 30-Nov 3; Paris

  111. Bonomi P, Greco A, Crawford J, et al. Results of a phase 2 trial of HGSETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/recurrent nonsmall cell lung cancer [abstract no. 1851]. 11th World Conference on Lung Cancer; 2005 Jul 3–6; Barcelona

  112. She QB, Solit DB, Ye Q, et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 2005; 8(4): 287–97

    Article  PubMed  CAS  Google Scholar 

  113. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005; 23(11): 2544–55

    Article  PubMed  CAS  Google Scholar 

  114. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005; 23(31): 7889–96

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by AIRC, 2006 (Italian Association for Cancer Research), Milan, Italy. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, P.za Giulio Cesare, 11, 70124, Bari, Italy

    Sabino Ciavarella, Annalisa Milano, Franco Dammacco &  Franco Silvestris

Authors
  1. Sabino Ciavarella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annalisa Milano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Franco Dammacco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Franco Silvestris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Franco Silvestris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciavarella, S., Milano, A., Dammacco, F. et al. Targeted Therapies in Cancer. BioDrugs 24, 77–88 (2010). https://doi.org/10.2165/11530830-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11530830-000000000-00000

Keywords

Search

Navigation