Targeted Drug Therapy in Pancreatic Cancer

  • Don L. Gibbons
  • Robert A. Wolff
  • Gauri Varadhachary
Part of the Current Clinical Oncology™ book series (CCO)

Abstract

Only modest progress has been made in improving the overall survival of pancreatic cancer patients during the past 20 years with standard cytotoxic chemotherapy drugs. More work needs to be done to address the key biologic characteristics of pancreatic cancer that make it so aggressive, metastasizing at an early stage, and more refractory to standard treatments than most other solid tumor types. Here, we discuss the emerging role of targeted therapy in pancreatic cancer and the status of currently available and tested agents. We also point out the potential pitfalls in current trial designs and recommend new methods for testing novel compounds in this heterogeneous and difficult-to-treat group of patients.

Key Words

Targeted therapy Pancreatic cancer Chemotherapy Clinical trials 

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References

  1. 1.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007;57(1):43–66.Google Scholar
  2. 2.
    Carter SK, Comis RL. The integration of chemotherapy into a combined modality approach for cancer treatment. VI. Pancreatic adenocarcinoma. Cancer Treat Rev 1975;2(3):193–214.PubMedCrossRefGoogle Scholar
  3. 3.
    Freeny PC. Radiology of the pancreas: two decades of progress in imaging and intervention. AJR Am J Roentgenol 1988;150(5):975–81.PubMedGoogle Scholar
  4. 4.
    Eckel F, Schneider G, Schmid RM. Pancreatic cancer: a review of recent advances. Expert Opin Invest Drugs 2006;15(11):1395–410.CrossRefGoogle Scholar
  5. 5.
    Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15(6):2403–13.Google Scholar
  6. 6.
    Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003;21(18):3402–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Saif MW. Pancreatic cancer: highlights from the 42nd annual meeting of the American Society of Clinical Oncology, 2006. JOP J Pancreas (Online) 2006;7(4):337–48.Google Scholar
  8. 8.
    Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23(15):3509–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24(24):3946–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Hezel AF, Kimmelman AC, Stanger BZ,et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20(10):1218–49.PubMedCrossRefGoogle Scholar
  11. 11.
    Yamano M, Fujii H, Takagaki T, et al. Genetic progression and divergence in pancreatic carcinoma. Am J Pathol 2000;156(6):2123–33.PubMedGoogle Scholar
  12. 12.
    Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer 2002;2(12):897–909.PubMedCrossRefGoogle Scholar
  13. 13.
    Olive KP, Tuveson DA. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res 2006;12(18):5277–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103(2):211–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37(suppl 4):S3–8.Google Scholar
  16. 16.
    Wells A. EGF receptor. Int J Biochem Cell Biol 1999;31(6):637–43.PubMedCrossRefGoogle Scholar
  17. 17.
    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(3):183–232.PubMedCrossRefGoogle Scholar
  18. 18.
    Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999;82(2–3):241–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2(2):127–37.PubMedCrossRefGoogle Scholar
  20. 20.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Korc M, Chandrasekar B, Yamanaka Y, et al. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 1992;90(4):1352–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Lemoine NR, Hughes CM, Barton CM, et al. The epidermal growth factor receptor in human pancreatic cancer. J Pathol 1992;166(1):7–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Yamanaka Y, Friess H, Kobrin MS, et al. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993;13(3):565–9.Google Scholar
  24. 24.
    Korc M, Friess H, Yamanaka Y, et al. Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor alpha, and phospholipase C gamma. Gut 1994;35(10):1468–73.PubMedCrossRefGoogle Scholar
  25. 25.
    Kwak EL, Jankowski J, Thayer SP, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 2006;12(14 Pt 1):4283–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 2004;22(13):2610–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol 2007;25(18S):LBA4509.Google Scholar
  28. 28.
    Kullmann F, Hollerbach S, Dollinger M, et al. Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in 1st line metastatic pancreatic cancer: first results from a multicenter phase II study. Presented at the American Society of Clinical Oncology, Gastrointestinal Cancers Symposium, 2007.Google Scholar
  29. 29.
    Moore MJ. Brief communication: a new combination in the treatment of advanced pancreatic cancer. Semin Oncol 2005;32(suppl 8):5–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Grunewald K, Lyons J, Frohlich A, et al. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer 1989;43(6):1037–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Klimstra DS, Longnecker DS. K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 1994;145(6):1547–50.PubMedGoogle Scholar
  32. 32.
    Lemoine NR, Jain S, Hughes CM, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992;102(1):230–6.PubMedGoogle Scholar
  33. 33.
    Lohr M, Kloppel G, Maisonneuve P, et al. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 2005;7(1):17–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Fleming JB, Shen GL, Holloway SE, et al. Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy. Mol Cancer Res 2005;3(7):413–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Pechlivanis M, Kuhlmann J. Hydrophobic modifications of Ras proteins by isoprenoid groups and fatty acids—more than just membrane anchoring. Biochim Biophys Acta 2006;1764(12):1914–31.PubMedGoogle Scholar
  36. 36.
    Resh MD. Trafficking and signaling by fatty-acylated and prenylated proteins. Nat Chem Biol 2006;2(11):584–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Cohen SJ, Ho L, Ranganathan S, et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 2003;21(7):1301–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Macdonald JS, McCoy S, Whitehead RP, et al. A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest Oncology Group (SWOG 9924) study. Invest New Drugs 2005;23(5):485–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22(8):1430–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285(21):1182–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006;312(5777):1171–5.Google Scholar
  42. 42.
    Ferrara N, Leung DW, Cachianes G, et al. Purification and cloning of vascular endothelial growth factor secreted by pituitary folliculostellate cells. Methods Enzymol 1991;198:391–405.PubMedCrossRefGoogle Scholar
  43. 43.
    Kiselyov A, Balakin KV, Tkachenko SE. VEGF/VEGFR signalling as a target for inhibiting angiogenesis. Expert Opin Invest Drugs 2007;16(1):83–107.CrossRefGoogle Scholar
  44. 44.
    Itakura J, Ishiwata T, Friess H, et al. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 1997;3(8):1309–16.PubMedGoogle Scholar
  45. 45.
    Itakura J, Ishiwata T, Shen B, et al. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer 2000;85(1):27–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Seo Y, Baba H, Fukuda T, et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000;88(10):2239–45.PubMedCrossRefGoogle Scholar
  47. 47.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 2006;28(11):1779–802.PubMedCrossRefGoogle Scholar
  49. 49.
    Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005;23(31):8033–40.PubMedCrossRefGoogle Scholar
  50. 50.
    Kindler H, Niedzwiecki D, Hollis E, et al. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB) 80303. Presented at the American Society of Clinical Oncology, Gastrointestinal Cancers Symposium, 2007.Google Scholar
  51. 51.
    Bloomston M, Zervos EE, Rosemurgy AS 2nd. Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials. Ann Surg Oncol 2002;9(7):668–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee KH, Hyun MS, Kim JR. Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis. Clin Exp Metastasis 2003;20(6):499–505.Google Scholar
  53. 53.
    Okada Y, Eibl G, Guha S, et al. Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin Exp Metastasis 2004;21(4):285–92.PubMedCrossRefGoogle Scholar
  54. 54.
    Tan X, Egami H, Abe M, et al. Involvement of MMP-7 in invasion of pancreatic cancer cells through activation of the EGFR mediated MEK-ERK signal transduction pathway. J Clin Pathol 2005;58(12):1242–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Bramhall SR, Neoptolemos JP, Stamp GW, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 1997;182(3):347–55.PubMedCrossRefGoogle Scholar
  56. 56.
    Haq M, Shafii A, Zervos EE, et al. Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer. Cancer Res 2000;60(12):3207–11.PubMedGoogle Scholar
  57. 57.
    Zervos EE, Norman JG, Gower WR, et al. Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo. J Surg Res 1997;69(2):367–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Bramhall SR, Rosemurgy A, Brown PD, et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001;19(15):3447–55.PubMedGoogle Scholar
  59. 59.
    Moore MJ, Hamm J, Dancey J, et al. 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 2003;21(17):3296–302.PubMedCrossRefGoogle Scholar
  60. 60.
    Wang W, Abbruzzese JL, Evans DB, et al. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999;5(1):119–27.PubMedGoogle Scholar
  61. 61.
    Yokoi K, Fidler IJ. Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine. Clin Cancer Res 2004;10(7):2299–306.PubMedCrossRefGoogle Scholar
  62. 62.
    Banerjee S, Zhang Y, Ali S, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res 2005;65(19):9064–72.Google Scholar
  63. 63.
    Mohammad RM, Banerjee S, Li Y, et al. Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts. Cancer 2006;106(6):1260–8.PubMedCrossRefGoogle Scholar
  64. 64.
    El-Rayes BF, Ali S, Ali IF, et al. Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB. Cancer Res 2006;66(21):10553–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Banerjee S, Zhang Y, Wang Z, et al. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int J Cancer 2007;120(4):906–17.PubMedCrossRefGoogle Scholar
  66. 66.
    Jimeno A, Rubio-Viqueira B, Amador ML, et al. Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 2005;65(8):3003–10.PubMedGoogle Scholar
  67. 67.
    Huang C, Cao J, Huang KJ, et al. Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci 2006;97(12):1417–23.PubMedCrossRefGoogle Scholar
  68. 68.
    Scholz A, Heinze S, Detjen KM, et al. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 2003;125(3):891–905.PubMedCrossRefGoogle Scholar
  69. 69.
    Toyonaga T, Nakano K, Nagano M, et al. Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer Lett 2003;201(1):107–16.PubMedCrossRefGoogle Scholar
  70. 70.
    Fahrig R, Steinkamp-Zucht A, Schaefer A. Prevention of adriamycin-induced mdr1 gene amplification and expression in mouse leukemia cells by simultaneous treatment with the anti-recombinogen bromovinyldeoxyuridine. Anticancer Drug Des 2000;15(5):307–12.PubMedGoogle Scholar
  71. 71.
    De Clercq E. Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster. Biochem Pharmacol 2004;68(12):2301–15.PubMedCrossRefGoogle Scholar
  72. 72.
    Fahrig R, Heinrich JC, Nickel B, et al. Inhibition of induced chemoresistance by cotreatment with (E)-5-(2-bromovinyl)-2’-deoxyuridine (RP101). Cancer Res 2003;63(18):5745–53.PubMedGoogle Scholar
  73. 73.
    Fahrig R, Quietzsch D, Heinrich JC, et al. RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients. Anticancer Drugs 2006;17(9):1045–56.PubMedCrossRefGoogle Scholar
  74. 74.
    Kunnumakkara AB, Guha S, Krishnan S, et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res 2007;67(8):3853–61.PubMedCrossRefGoogle Scholar
  75. 75.
    Dhillon N, Wolff RA, Abbruzzese JL, et al. Phase II clinical trial of curcumin in patients with advanced pancreatic cancer. J Clin Oncol 2007;24(18S):14151.Google Scholar
  76. 76.
    Vande Velde C, Cizeau J, Dubik D, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 2000;20(15):5454–68.PubMedCrossRefGoogle Scholar
  77. 77.
    Akada M, Crnogorac-Jurcevic T, Lattimore S, et al. Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer. Clin Cancer Res 2005;11(8):3094–101.PubMedCrossRefGoogle Scholar
  78. 78.
    Erkan M, Kleeff J, Esposito I, et al. Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene 2005;24(27):4421–32.PubMedCrossRefGoogle Scholar
  79. 79.
    Abe T, Toyota M, Suzuki H, et al. Upregulation of BNIP3 by 5-aza-2’-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death. J Gastroenterol 2005;40(5):504–10.PubMedCrossRefGoogle Scholar
  80. 80.
    Kanda T, Tada M, Imazeki F, et al. 5-Aza-2’-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. Oncol Rep 2005;14(4):975–9.PubMedGoogle Scholar
  81. 81.
    Hochster HS, Haller DG, de Gramont A, et al. Consensus report of the International Society of Gastrointestinal Oncology on therapeutic progress in advanced pancreatic cancer. Cancer 2006;107(4):676–85.PubMedCrossRefGoogle Scholar
  82. 82.
    Boeck S, Hinke A, Wilkowski R, et al. Importance of performance status for treatment outcome in advanced pancreatic cancer. World J Gastroenterol 2007;13(2):224–7.PubMedGoogle Scholar
  83. 83.
    Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 2003;16(9):902–12.PubMedCrossRefGoogle Scholar
  84. 84.
    Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997;57(9):1731–4.PubMedGoogle Scholar
  85. 85.
    Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–3.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, Totowa, NJ 2008

Authors and Affiliations

  • Don L. Gibbons
  • Robert A. Wolff
  • Gauri Varadhachary

There are no affiliations available

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