Antiangiogenic Strategies in Pancreatic Cancer

  • Hanno Riess
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 177)


Since the introduction of gemcitabine in the treatment of pancreatic cancer, progress in the use of combination chemotherapies has been very limited. Of the different novel options, antiangiogenic treatment strategies are among those being intensively studied in preclinical and clinical settings of adenocarcinoma of the pancreas. Phase I and limited-size phase II studies using drugs with antiangiogenic properties have reported encouraging results. Overall, the results of phase III studies with some metalloprotease inhibitors and bevacizumab have so far failed to demonstrate a survival benefit for these drugs. Further investigations that will take into account the heterogeneity of pancreatic cancer are warranted using these or other antiangiogenic active substances.


Vascular Endothelial Growth Factor Epidermal Growth Factor Receptor Pancreatic Cancer Clin Oncol Human 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.
    Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, Mercurio AM (2003) Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63:5230–5233PubMedGoogle Scholar
  2. 2.
    Baker CH, Solorzano CC, Fidler IJ (2002) Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res 2002 62:1996–2003Google Scholar
  3. 3.
    Blanquicett C, Saif MW, Buchsbaum DJ, Eloubeidi M, Vickers SM, Chhieng DC, et al. (2005) Antitumor efficacy of capecitabine and celecoxib in irradiated and lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: clinical implications of abscopal effects. Clin Cancer Res 11:8773–8781PubMedCrossRefGoogle Scholar
  4. 4.
    Bockhorn M, Tsuzuki Y, Xu L, et al. (2003) Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. Clin Cancer Res 9:4221–4226PubMedGoogle Scholar
  5. 5.
    Bramhall SR, Rosemurgy A, Brown PD, Bowry C, et al. (2001) Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19:3447–3455PubMedGoogle Scholar
  6. 6.
    Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA (2002) A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161–167PubMedCrossRefGoogle Scholar
  7. 7.
    Brophy JM (2005) Celecoxib and cardiovascular risks. Expert Opin Drug Saf 4:1005–1015PubMedCrossRefGoogle Scholar
  8. 8.
    Buchler P, Reber HA, Buchler MW, et al. (2002) VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg 236:738–749PubMedCrossRefGoogle Scholar
  9. 9.
    Buchler P, Reber HA, Ullrich A, et al. (2003) Pancreatic cancer growth is inhibited by blockade of VEGF-RII. Surgery 134:772–782PubMedCrossRefGoogle Scholar
  10. 10.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  11. 11.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–669PubMedCrossRefGoogle Scholar
  12. 12.
    Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270PubMedCrossRefGoogle Scholar
  13. 13.
    Chirivi RG, Garofalo A, Crimmin MJ, Bawden LJ, Stoppacciaro A, Brown PD, Giavazzi R (1994) Inhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int J Cancer 58:460–464PubMedCrossRefGoogle Scholar
  14. 14.
    Crane CH, Ellis M, Abbruzzese JL, Douglas EB, Henry X, Ho L, et al. (2005) Phase I trial of bevacizumab (BV) with concurrent radiotherapy (RT) and capecitabine (CAP) in locally advanced pancreatic adenocarcinoma (PA). J Clin Oncol 23 [Suppl]:4033Google Scholar
  15. 15.
    Densmore JJ, Fox JR, Kannarkat G, Morgan JK, Petroni G, Blount T, et al. (2005) A Phase I/II trial of weekly gemcitabine with celecoxib and thalidomide for patients with advanced pancreatic cancer. J Clin Oncol 23 [Suppl]:4241Google Scholar
  16. 16.
    Dredge K, Marriott JB, Dalgleish AG (2002) Immunological effects of thalidomide and its chemical and functional analogs. Crit Rev Immunol 22:425–437PubMedGoogle Scholar
  17. 17.
    Dutcher JP (2004) Mammalian target of rapamycin inhibition. Clin Cancer Res 10:6382S–6387SPubMedCrossRefGoogle Scholar
  18. 18.
    Eccles SA, Box GM, Court WJ, Bone EA, Thomas W, Brown PD (1996) Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). Cancer Res 56:2815–2822PubMedGoogle Scholar
  19. 19.
    Erlichman C, Adjei AA, Alberts SR, Sloan JA, Goldberg RM, Pitot HC, et al. (2001) Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566. Ann Oncol 12:389–395PubMedCrossRefGoogle Scholar
  20. 20.
    Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3:643–651PubMedCrossRefGoogle Scholar
  21. 21.
    Fujimoto K, Hosotani R, Wada M, Lee JU, Koshiba T, Miyamoto Y, et al. (1998) Expression of two angiogenic factors, vascular endothelial growth factor and platelet-derived endothelial cell growth factor in human pancreatic cancer, and its relationship to angiogenesis. Eur J Cancer 34:1439–1447PubMedCrossRefGoogle Scholar
  22. 22.
    Gatto C, Rieppi M, Borsotti P, Innocenti S, Ceruti R, Drudis T, et al. (1999) BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin Cancer Res 5:3603–3607PubMedGoogle Scholar
  23. 23.
    Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM (2005) Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54:540–545PubMedCrossRefGoogle Scholar
  24. 24.
    Heath EI, O‘Reilly S, Humphrey R, Sundaresan P, Donehower RC, Sartorius S, et al. (2001) Phase I trial of the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours. Cancer Chemother Pharmacol 48:269–274PubMedCrossRefGoogle Scholar
  25. 25.
    Hirte H, Goel R, Major P, Seymour L, Huan S, Stewart D, et al. (2000) A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours. Ann Oncol 11:1579–1584PubMedCrossRefGoogle Scholar
  26. 26.
    Honda M, Mori M, Ueo H, Sugimachi K, Akiyoshi T (1996) Matrix metalloproteinase-7 expression in gastric carcinoma. Gut 39:444–448PubMedCrossRefGoogle Scholar
  27. 27.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
  28. 28.
    Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW, Korc M (1997) Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 3:1309–1316PubMedGoogle Scholar
  29. 29.
    Itakura J, Ishiwata T, Shen B, et al. (2000) Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer 85:27–34PubMedCrossRefGoogle Scholar
  30. 30.
    Javle MM, Iyer RV, Yu J, et al. (2006) Phase II study of gemcitabine, capecitabine and bevacizumab for advanced pancreatic cancer (APC) with ECOG PS 0-1 (abstr). Proc Am Soc Clin Oncol 24:4117Google Scholar
  31. 31.
    Kato H, Ishikura H, Kawarada Y, Furuya M, Kondo S, Kato H, Yoshiki T (2001) Anti-angiogenic treatment for peritoneal dissemination of pancreas adenocarcinoma: a study using TNP-470. Jpn J Cancer Res 92:67–73PubMedGoogle Scholar
  32. 32.
    Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, Vokes E (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8804PubMedCrossRefGoogle Scholar
  33. 33.
    Kindler HL, Bylow KA, Hochster HS, et al. (2006) A randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis (abstr). Proc Am Soc Clin Oncol 24:4040Google Scholar
  34. 34.
    Kindler HL, Niedzwiecki D, Hollis D, et al. (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) vs gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB) 80 303 (abstr). Proc Gastrointest Cancers Symp 139:108Google Scholar
  35. 35.
    Ko AH, Dito E, Schillinger B, et al. (2006) A phase II study of gemcitabine (GEM) given at fixed-dose rate (FDR) infusion, low-dose cisplatin (CDDP), and bevacizumab in metastatic pancreatic cancer (PanCa) (abstr). Proc Am Soc Clin Oncol 24:4041Google Scholar
  36. 36.
    Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, et al. (2003) Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296–3302PubMedCrossRefGoogle Scholar
  37. 37.
    Niedergethmann M, Hildenbrand R, Wostbrock B, Hartel M, Sturm JW, Richter A, Post S (2002) High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas 25:122–129PubMedCrossRefGoogle Scholar
  38. 38.
    Nomura H, Sato H, Seiki M, Mai M, Okada Y (1995) Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res 55:3263–3266PubMedGoogle Scholar
  39. 39.
    Raut CP, Nawrocki S, Lashinger LM, Davis DW, Khanbolooki S, Xiong H, et al. (2004) Celecoxib inhibits angiogenesis by inducing endothelial cell apoptosis in human pancreatic tumor xenografts. Cancer Biol Ther 3:1217–1224PubMedCrossRefGoogle Scholar
  40. 40.
    Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K (2000) High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88:2239–2245PubMedCrossRefGoogle Scholar
  41. 41.
    Sier CF, Kubben FJ, Ganesh S, Heerding MM, Griffioen G, Hanemaaijer R, et al. (1996) Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer 74:413–417PubMedGoogle Scholar
  42. 42.
    Stephan S, Datta K, Wang E, Li J, Brekken RA, Parangi S, Thorpe PE, Mukhopadhyay D (2004) Effect of rapamycin alone and in combination with antiangiogenesis therapy in an orthotopic model of human pancreatic cancer. Clin Cancer Res 15:6993–7000CrossRefGoogle Scholar
  43. 43.
    Teo SK, Stirling DI, Zeldis JB (2005) Thalidomide as a novel therapeutic agent: new uses for an old product. Drug Discov Today 10:107–114PubMedCrossRefGoogle Scholar
  44. 44.
    Tonra JR, Deevi DS, Corcoran E, Li H, Wang S, Carrick FE, Daniel JH (2006) Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy. Clin Cancer Res 1:2197–2207CrossRefGoogle Scholar
  45. 45.
    Vacca A, Scavelli C, Montefusco V, Di Pietro G, Neri A, Mattioli M, et al. (2005) Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J Clin Oncol 23:5334–5346PubMedCrossRefGoogle Scholar
  46. 46.
    Von Marshall Z, Cramer T, Hocker M, et al. (2000) De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. Gastroenterology 119:1358–1372CrossRefGoogle Scholar
  47. 47.
    Wang HX, Chen QK (2003) Expression and significance of cyclooxygenase-2 in human pancreatic carcinomas. Ai Zheng 22:649–652PubMedGoogle Scholar
  48. 48.
    Watson SA, Morris TM, Collins HM, Bawden LJ, Hawkins K, Bone EA (1999) Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA. Br J Cancer 81:19–23PubMedCrossRefGoogle Scholar
  49. 49.
    Whittaker M, Floyd CD, Brown P, Gearing AJ (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99:2735–2776PubMedCrossRefGoogle Scholar
  50. 50.
    Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, et al. (2003) Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer 88:1979–1986PubMedCrossRefGoogle Scholar
  51. 51.
    Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147PubMedCrossRefGoogle Scholar
  52. 52.
    Xiong HQ, Hess KR, Kayaleh OR, Goodwin JW, Banerjee T, Sinclair SS, et al. (2005) A phase II trial of gemcitabine and celecoxib for metastatic pancreatic cancer. J Clin Oncol 23:4174Google Scholar
  53. 53.
    Zhou XC, Tang CW, Liu CL, Wang CH (2004) Effects of rofecoxib on angiogenesis of pancreatic cancer xenograft in nude mice. Ai Zheng 23:376–380PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Hanno Riess
    • 1
  1. 1.Medizinische Klinik mit Schwerpunkt Hämatologie und OnkologieCharité – Universitätsmedizin Berlin, Campus Virchow-KlinikumBerlinGermany

Personalised recommendations