Targeting Small Molecules in Cancer

  • Harold J. Wanebo
  • David Berz
  • Anthony Mega
Part of the Cancer Treatment and Research book series (CTAR, volume 135)

The ability of tumors to induce new blood vessel formation, which potentiates tumor growth and the concept of counteracting this growth by blocking angiogenesis, has been known for multiple decades (1–3).


Epidermal Growth Factor Receptor Clin Oncol Metastatic Colorectal Cancer Metastatic Renal Cell Carcinoma Advanced Pancreatic 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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med 285:1182–1186, 1971.PubMedCrossRefGoogle Scholar
  2. 2.
    Greene HSN: Heterologous transplantation of mammalian tumors. I. The transfer of rabbit tumors to alien species. J Exper Med 73:461–471, 1941.CrossRefGoogle Scholar
  3. 3.
    Jain RK, PhD. Antiangiogenic therapy for cancers: Current and emerging concepts. Oncology Suppliment No. 3, April 2005, p 7–16.Google Scholar
  4. 4.
    Carmeliet P, Jain RK. Angiogenesis in cancers and other diseases. Nature 407:249–257, 2005.CrossRefGoogle Scholar
  5. 5.
    Jain RK, PhD. Antiangiogenic therapy for cancers: Current and emerging concepts. Oncol April, 2005, Suppliment No.3.Google Scholar
  6. 6.
    Heinz-Joseph Lenz. Antiangiogenic agents in cancer therapy. Oncol Supplement No.3, Page 17–25, 2005.Google Scholar
  7. 7.
    Kerbal R, Folkman J: Clinical translation of angiogenensis inhibitors: Nat Rev Cancer.Google Scholar
  8. 8.
    Hicklin DJ, Ellis LM: Role of the vascular endolethelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027, 2005.PubMedCrossRefGoogle Scholar
  9. 9.
    Bachelder RE, Lispcomb EA, Lin X, et al. Competing autocrine pathways involving Alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63:5230–5233, 2003.PubMedGoogle Scholar
  10. 10.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotcan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Eng J Med 350:2335–2342, 2004.CrossRefGoogle Scholar
  11. 11.
    Gille H, Kowalski J, Li B, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGF-1) and KDR (VEGF-2). A reassessment of using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276:3222–30, 2001.PubMedCrossRefGoogle Scholar
  12. 12.
    Bachelder RE, Crago A, CVhung J, et al: Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer res 61: 5736–5740, 2001.PubMedGoogle Scholar
  13. 13.
    Li M, Yang H, Chai H, et al: Pancreatic carcinoma cells express neuropilins and vascular endothelial growth factor, but not vascular endothelial growth factor receptors. Cancer 101–2341-2350, 2004.PubMedCrossRefGoogle Scholar
  14. 14.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotcan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Eng J Med 350:2335–2342, 2004.CrossRefGoogle Scholar
  15. 15.
    Johnson DH, Fehrenbacher L, Novotny W, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer.J Clin Oncology 22:2184–2191, 2004.CrossRefGoogle Scholar
  16. 16.
    Miller KD, Chap LI, Holmes MA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients previously treated with breast cancer. J Clin Oncology23: 792–799, 2005.CrossRefGoogle Scholar
  17. 17.
    Salz LB, Lenz H, Kindler H, et al. Interim report of Randomized phase II trial of cetuxmiab/bevacizumab/irinotecan (CBI) vs. cetuximab/bevacizumab in irinotecan-refractory colorectal cancer (abstract 169b). Gastrointestinal Cancers Symposiuim, 2005.Google Scholar
  18. 18.
    Dickler M, Rugo H, Caravella, et al. Phase II trial of erlotinib (OSI–774) an epidermal growth factor receptor tyrosine kinase inhibitor and bezacizumab a recominent Moab to VEGF in Metastatic Breast Cancer patients. Proc ASCO 23:127, 2004.Google Scholar
  19. 19.
    Hainsworth JD, Sosman JA, Spigel DR, et al. Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC) (abstract 4502). Proc. Am Soc Clin Oncol 23:381, 2004.Google Scholar
  20. 20.
    Sandler AB, Blumenschein GR, Henderson T, et al. Phase I/II trial evaluating the anti-VEGF Mab bevacizumab in combination with erlotinib, a HER1/EGFR-TK inhibitor, for patients with recurrent non-small cell lung cancer (abstract 2000). Proc. Am Soc Clin Oncol 23:127, 2004.Google Scholar
  21. 21.
    Upont J, Schwartz L, Koutcher D, et al. Phase I and pharmacokinetics study of VEGF Trap administered subcutaneously (SC) to patients (Pts) with advanced solid malignancies. Abstract 3009, Proc AM Soc Clin Oncol 23:197, 2004.Google Scholar
  22. 22.
    Levine AM, Quinn DI, Gorospe G, et al. Phase I trial of anti-sense oligonucleotide vascular enthelial growth factor (VEGF-AS, Veglin) in patients with relapsed and refractory malignancies (abstract 3008). Proc. Am SocClin Oncol 23:197, 2004.Google Scholar
  23. 23.
    Schleucher N, Trarbach T, Junker U, et al. Phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor in combination with FOLFIRI as first-line treatment for patiets with metastatic colorectal cancer (abstract 3558). Proc. Am Soc Clin Oncol 23:260, 2004.Google Scholar
  24. 24.
    Steward WP, Thomas A, Morgan B, et al. Expanded phase I/II study of PTK787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in combination with FOLFOX-4 as first-line treatment for patients with metastatic colorectal cancer (abstract 3556). Proc. Am Soc Clin Oncol 23:259, 2004.Google Scholar
  25. 25.
    Rosen L, Mulay M, Long J, et al. Phase I trial of SU011248, a novel tyrosine kinase Inhibitor in advanced solid tumors (abstract 765). Proc. Am Soc Clin Oncol 22:191, 2003.Google Scholar
  26. 26.
    Lara PN Jr, Quinn DI, Margolin K, et al. SU5416 plus interferon alpha in advanced renal cell carcinoma: A phase II California Cancer Consortium study with biological and imaging correlates of angiogenesis inhibition. Clin Cancer Res 9:4772–4781, 2003.PubMedGoogle Scholar
  27. 27.
    Brahmer JR, Kelsey S, Scigalla P, et al. A phase II study of SU6668 in patients with Refractory solid tumors (abstract 335). Proc. Am Soc Clin Oncol 21:84a, 2002.Google Scholar
  28. 28.
    Ratain MJ, Flaherty KT, Stadker WM, et al. Preliminary antitumor activity of BAY 43–9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT) (abstract 4501). Proc Am Soc Clin Oncol 23:381, 2004.Google Scholar
  29. 29.
    Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 353: 2477–2490, 2005.PubMedCrossRefGoogle Scholar
  30. 30.
    Lam JS, Leppert JT, Figlin RA, et al: Surviellance following radical or partial nephrectomy for renal cell cancer. Curr Urol Rep 6: 7–18, 2005.PubMedCrossRefGoogle Scholar
  31. 31.
    Kavolius JP, Mastorakos DP, Pavlovich C, et al: Resection of metastatic renal cell carcinoma. J Clin Oncol 16: 2261–2266, 1998.PubMedGoogle Scholar
  32. 32.
    Fyfe G, Fisher RI, Rosenberg SA, et al: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant IL-2 therapy. J Clin Oncol 13: 688–696, 1995.PubMedGoogle Scholar
  33. 33.
    Motzer RJ, Rini B, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295: 2516–2524, 2005.CrossRefGoogle Scholar
  34. 34.
    Awada A, Hendlisz A, gil T et al: Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7days off in patients with advanced, refractory solid tumours. Br J Cancer 92: 1855–1861, 2005.PubMedCrossRefGoogle Scholar
  35. 35.
    Clark JW, Eder JP, Ryan D, et al: Safety and pharmacokinetics of the dual action raf kinase and VEGF receptor inhibitor, BAY 43–9006, in patients with refractory, advanced solid tumors. Clin Cancer Res 11: 5472–5480, 2005.PubMedCrossRefGoogle Scholar
  36. 36.
    Strumberg D, Richly H, Hilger RA, et al: Phase I clinical and pharmacokinetic study of the novel Raf kinase and VEGF receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 23: 965–972, 2005.PubMedCrossRefGoogle Scholar
  37. 37.
    Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 19 (56): 6550–6565, 2000.PubMedCrossRefGoogle Scholar
  38. 38.
    Baselga J, Arteaga CL: Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23 (11):2445–2459, 2005.PubMedCrossRefGoogle Scholar
  39. 39.
    Schessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211–225.CrossRefGoogle Scholar
  40. 40.
    Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling nertwork: receptor heterodimerization in development and cancer. EMBO J 2000;19:3159–3167.PubMedCrossRefGoogle Scholar
  41. 41.
    Prenzel N, Fischer OM, Streit S, et al. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 2001;8:11.PubMedCrossRefGoogle Scholar
  42. 42.
    Slichenmyer WJ, Fry DW. Anticancer therapy targeting the erbB family receptor tyrosine kinases. Semin Oncol 2001;28 (suppl 16):67–79.PubMedCrossRefGoogle Scholar
  43. 43.
    Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001;411:355–365.PubMedCrossRefGoogle Scholar
  44. 44.
    Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science 1995;267:1782–1788.PubMedCrossRefGoogle Scholar
  45. 45.
    Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 2000;60 (suppl 1):15–23; discussion 41–42.Google Scholar
  46. 46.
    Moghol N, Sternberg PW. Mutiple positive and negative regulators of signaling by the EGF-receptor. Curr Opin Cell Biol 1999;11:190–196.CrossRefGoogle Scholar
  47. 47.
    Hackel PO, Zwick E, Prenzel N et al. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 1999;11:184–189.PubMedCrossRefGoogle Scholar
  48. 48.
    Levitzki A, Protein tyrosine kinase inhibitors as novel therapeutic agents.Pharmacol. Ther. 1999;82, 231–239.Google Scholar
  49. 49.
    Bender JG, Cooney EM, Kandel JJ, Yamashiro DJ. Vascular remodeling and clinical resistance to antiangiogenic cancer therapy. Drug Resist. Upgrade. 2004;7, 289–300.CrossRefGoogle Scholar
  50. 50.
    Yarden Y. The EGFR family and its ligands in human cancer: signaling mechanisms and the therapeutic opportunities.Eur. J. Cancer. 2001; 37 (Suppl 4):S3–S8.Google Scholar
  51. 51.
    Iwata K, Provoncha K, Gibson N. Inhibition of mutant EGFRvIII transformed cells by tyrosine kinase inhibitor OSI-774 (Tarceva). Presented at the annual meeting of the American Society of Clinical Oncology, 2002. Abstract 79.Google Scholar
  52. 52.
    Moyer JD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358, 774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 1997; 57: 4838–4848.PubMedGoogle Scholar
  53. 53.
    Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL.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 Jan 1;22(1):77–85.Google Scholar
  54. 54.
    Hidalgo M. Erlotinib: preclinical investigations. Oncology (Huntingt). 2003; 17: 11–16.Google Scholar
  55. 55.
    Durkin AJ, Osborne DA, Yeatman TJ, Rosemurgy AS, Armstrong C, Zervos EE EGF receptor antagonism improves survival in a murine model of pancreatic adenocarcinoma J Surg Res. 2006 Sep;135(1):195–201.PubMedCrossRefGoogle Scholar
  56. 56.
    Ng, M.S. Tsao and T. Nicklee et al., Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma, Mol. Cancer Ther. 1 (2002), pp. 777–783.Google Scholar
  57. 57.
    R. S. Herbst, D. Prager, R. Hermann 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); Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 7011.Google Scholar
  58. 58.
    U. Gatzemeier, A. Pluzanska, A. Szczesna 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); Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 7010.Google Scholar
  59. 59.
    Shepard FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl J Med 2005; 353:123–132.CrossRefGoogle Scholar
  60. 60.
    J. Moore, Brief communication: a new combination in the treatment of Engl J Med. 2005; 353: 123–132.Google Scholar
  61. 61.
    Chinnaiyan S, Huang S, Armstrong E, et al. Radiosensitization following EGFR signaling inhibition by erlotinib (Tarceva). Int J Rad Onc Biol Phys. 2003;57(suppl 1):S294.Google Scholar
  62. 62.
    Harari P, Huang SM. Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):976–83.PubMedGoogle Scholar
  63. 63.
    D. Iannitti, T. Dipetrillo and P. Akerman et al., Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a Phase I study, Am. J. Clin. Oncol. 28 (2005), pp. 570–575.PubMedCrossRefGoogle Scholar
  64. 64.
    J. S. Kortmansky, E. M. O’Reilly, B. D. Minsky et al. A phase I trial of erlotinib, gemcitabine and radiation for patients with locally-advanced, unresectable pancreatic cancer; Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 4107.Google Scholar
  65. 65.
    Erlichman, C., Hidalgo, M., Boni et al. Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol. (24) 115:2225–6, 2006.Google Scholar
  66. 66.
    Cappuzzo, F, Varella-Garcia, M, Shigematsu, H, et al. Increased HER2 Gene Copy Number Is Associated With Response to Gefitinib Therapy in Epidermal Growth Factor Receptor-Positive Non-Small-Cell Lung Cancer Patients. J Clin Oncol 2005; 23:5007.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar
  68. 68.
    Janne, PA, Gurubhagavatula, S, Yeap, BY, et al. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study. Lung Cancer 2004; 44:221.PubMedCrossRefGoogle Scholar
  69. 69.
    Lynch, TJ, Bell, DW, Sordella, R, et al. Activating mutations in the epidermal growth factor receptor underlying aresponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129.PubMedCrossRefGoogle Scholar
  70. 70.
    Tokumo, M, Toyooka, S, Kiura, K, et al. The Relationship between Epidermal Growth Factor Receptor Mutations and Clinicopathologic Features in Non-Small Cell Lung Cancers. Clin Cancer Res 2005; 11:1167.PubMedGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Aviel-Ronen, S, Fiona H, Blackhall FH, Shepherd, FA, Tsao, MS. K-ras Mutations in Non-Small-Cell Lung Carcinoma: A Review. Clin Lung Cancer 2006; 8:30.Google Scholar
  73. 73.
    Tsao, M, Zhu, C, Sakurada, A, et al. An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer (abstract). J Clin Oncol 2006; 24:365.CrossRefGoogle Scholar
  74. 74.
    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. J Clin Oncol 2003; 21:2237.PubMedCrossRefGoogle Scholar
  75. 75.
    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; 23:2544.PubMedCrossRefGoogle Scholar
  76. 76.
    Giaccone, G, Herbst, RS, Manegold, C, et al. Gefitinib in Combination With Gem citabine and Cisplatin in Advanced Non-Small-Cell Lung Cancer: A Phase III Trial–INTACT 1. J Clin Oncol 2004; 22:777.PubMedCrossRefGoogle Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar
  78. 78.
    Matsumori, Y, Yano, S, Goto, H. et al. ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase inhibits growth of experimental Lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model. Oncol Res. 2006;16(1):15–26.Google Scholar
  79. 79.
    Natale, RB, Bodkin, D, Govindan, R, et al. ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, Randomized Phase II Trial (abstract). J Clin Oncol 2006; 24:364s.Google Scholar
  80. 80.
    Heymach JV, Johnson BE, Prager D., et al. A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Followup results (Abstract) J Clin Oncol 2006; 24:368.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Harold J. Wanebo
    • 1
  • David Berz
    • 2
  • Anthony Mega
    • 3
  1. 1.Boston UniversityBostonUSA
  2. 2.Hematology and OncologyBrown UniversityProvidenceUSA
  3. 3.Medical OncologyBrown UniversityProvidenceUSA

Personalised recommendations