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  • Review Article
  • Published:

Pancreatic cancer: molecular pathogenesis and new therapeutic targets

Nature Reviews Gastroenterology & Hepatology volume 6, pages 412–422 (2009)Cite this article

A Correction to this article was published on 01 August 2009

Abstract

Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. Over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated modest survival benefit in combination with gemcitabine in a phase III clinical trial. Whilst the failures of targeted therapies in the clinical setting are discouraging, lessons have been learnt and new therapeutic targets that hold promise for the future management of the disease are continuously emerging. This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.

Key Points

  • Pancreatic cancer has high morbidity and mortality and is resistant to conventional treatment; therefore, an unmet need for novel therapeutic approaches exists

  • Important molecular pathways and components involved in pancreatic carcinogenesis have been targeted with therapeutic intent, including Ras, EGFR, VEGF, gastrin and matrix metalloproteinases

  • Good results from novel therapies have been demonstrated in vitro and in animal models, but results from the limited number of clinical trials are less encouraging

  • Erlotinib, an EGFR tyrosine kinase inhibitor, is the only agent so far that has shown a significant (albeit small) survival benefit in a phase III clinical trial

  • Potential therapeutic targets that warrant further investigation include other signal-transduction and embryonic pathways, telomerase, microRNAs and cancer stem cells

  • Future development of targeted treatments should focus on inhibition of multiple signaling pathways, or blockade of one signaling pathway at multiple levels

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Figure 1: The pathways and processes involved in pancreatic carcinogenesis.
Figure 2: A simplified representation of oncogenic signaling cascades in pancreatic cancer.

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References

  1. Jemal, A. et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).

    PubMed  Google Scholar 

  2. Pancreatic section, British Society of Gastroenterology et al. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut 54 (Suppl. 5), v1–v16 (2005).

  3. Burris, H. A. 3rd 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. 15, 2403–2413 (1997).

    CAS  PubMed  Google Scholar 

  4. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).

    CAS  PubMed  Google Scholar 

  6. Toubaji, A. et al. Pilot study of mutant Ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol. Immunother. 57, 1413–1420 (2008).

    CAS  PubMed  Google Scholar 

  7. Gjertsen, M. K. et al. Intradermal Ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int. J. Cancer 92, 441–450 (2001).

    CAS  PubMed  Google Scholar 

  8. Achtar, M. S. et al. Phase II clinical trial of mutant Ras peptide vaccine in combination with GM-CSF and IL-2 in advanced cancer patients [Abstract]. J. Clin. Oncol. 25, a3067 (2007).

    Google Scholar 

  9. Van Cutsem, E. et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22, 1430–1438 (2004).

    CAS  PubMed  Google Scholar 

  10. Martin, N. E. et al. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778 123 and radiotherapy for locally advanced pancreatic cancer. Clin. Cancer Res. 10, 5447–5454 (2004).

    CAS  PubMed  Google Scholar 

  11. Doss, H. H. et al. A phase I trial of romidepsin in combination with gemcitabine in patients with pancreatic and other advanced solid tumors [Abstract]. J. Clin. Oncol. 26, a2567 (2008).

    Google Scholar 

  12. Rudek, M. A. et al. Integrated development of S-trans. Trans-farnesylthiosalicyclic acid (FTS, salisarib) in pancreatic cancer [Abstract]. J. Clin. Oncol. 26, a4626 (2008).

    Google Scholar 

  13. Alberts, S. R. et al. Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J. Clin. Oncol. 22, 4944–4950 (2004).

    CAS  PubMed  Google Scholar 

  14. Rejiba, S., Wack, S., Aprahamian, M. & Hajri, A. K-ras oncogene silencing strategy reduces tumor growth and enhances gemcitabine chemotherapy efficacy for pancreatic cancer treatment. Cancer Sci. 98, 1128–1136 (2007).

    CAS  PubMed  Google Scholar 

  15. Brummelkamp, T. R., Bernards, R. & Agami, R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243–247 (2002).

    CAS  PubMed  Google Scholar 

  16. Rinehart, J. et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J. Clin. Oncol. 22, 4456–4462 (2004).

    CAS  PubMed  Google Scholar 

  17. Jimeno, A. et al. Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Mol. Cancer Ther. 6, 1079–1088 (2007).

    CAS  PubMed  Google Scholar 

  18. Takayama, Y. et al. MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth. Cancer Lett. 264, 241–249 (2008).

    CAS  PubMed  Google Scholar 

  19. Korc, M. 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. 90, 1352–1360 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bloomston, M., Bhardwaj, A., Ellison, E. C. & Frankel, W. L. Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique. Dig. Surg. 23, 74–79 (2006).

    CAS  PubMed  Google Scholar 

  21. Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).

    CAS  PubMed  Google Scholar 

  22. Grubbs, S. S., Grusenmeyer, P. A., Petrelli, N. J. & Gralla, R. J. Is it cost-effective to add erlotinib to gemcitabine in advanced pancreatic cancer? [Abstract]. J. Clin. Oncol. 24, a6048 (2006).

    Google Scholar 

  23. Fountzilas, G. et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Invest. 26, 784–793 (2008).

    CAS  PubMed  Google Scholar 

  24. Ignatiadis, M. et al. A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology 71, 159–163 (2006).

    CAS  PubMed  Google Scholar 

  25. Blaszkowsky, L. S. et al. A phase II study of docetaxel in combination with ZD1839 (gefitinib) in previously treated patients with metastatic pancreatic cancer [Abstract]. J. Clin. Oncol. 25, a15080 (2007).

    Google Scholar 

  26. Safran, H. et al. Lapatinib/gemcitabine and lapatinib/gemcitabine/oxaliplatin: a phase I study for advanced pancreaticobiliary cancer. Am. J. Clin. Oncol. 31, 140–144 (2008).

    CAS  PubMed  Google Scholar 

  27. Midgley, R. et al. Phase I study of GW572016 (lapatinib), a dual kinase inhibitor, in combination with irinotecan (IR), 5-fluorouracil (FU) and leucovorin (LV). J. Clin. Oncol. 23, 3086–3093 (2005).

    Google Scholar 

  28. Philip, P. A. 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 [Abstract]. J. Clin. Oncol. 25, 4509 (2007).

    Google Scholar 

  29. Cascinu, S. et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 9, 39–44 (2008).

    CAS  PubMed  Google Scholar 

  30. Munter, M. et al. Final results of a phase II trial [PARC-Study ISRCTN56652283] for patients with primary inoperable locally advanced pancreatic cancer combining intensity modulated radiotherapy (IMRT) with cetuximab and gemcitabine [Abstract]. J. Clin. Oncol. 26, 4613 (2008).

    Google Scholar 

  31. Burtness, B. A. et al. Phase II ECOG trial of irinotecan/docetaxel with or without cetuximab in metastatic pancreatic cancer: updated survival and CA19–19 results [Abstract]. J. Clin. Oncol. 26, 4642 (2008).

    Google Scholar 

  32. Caplin, M. et al. Expression and processing of gastrin in pancreatic adenocarcinoma. Br. J. Surg. 87, 1035–1040 (2000).

    CAS  PubMed  Google Scholar 

  33. Chau, I. et al. Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials. Br. J. Cancer 94, 1107–1115 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kawasaki, D. et al. Effect of Z-360, a novel orally active CCK-2/gastrin receptor antagonist on tumor growth in human pancreatic adenocarcinoma cell lines in vivo and mode of action determinations in vitro. Cancer Chemother. Pharmacol. 61, 883–892 (2008).

    CAS  PubMed  Google Scholar 

  35. Meyer, T. et al. A phase IB/IIA, multicentre, randomised, double-blind placebo controlled study to evaluate the safety and pharmacokinetics of Z-360 in subjects with unresectable advanced pancreatic cancer in combination with gemcitabine [Abstract]. J. Clin. Oncol. 26, 4636 (2008).

    Google Scholar 

  36. Shapiro, J. et al. G17DT + gemcitabine [Gem] versus placebo + Gem in untreated subjects with locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas: results of a randomized, double-blind, multinational, multicenter study [Abstract]. J. Clin. Oncol. 23, 4012 (2005).

    Google Scholar 

  37. Seo, Y., Baba, H., Fukuda, T., Takashima, M. & Sugimachi, K. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88, 2239–2245 (2000).

    CAS  PubMed  Google Scholar 

  38. Kindler, H. L. 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). J. Clin. Oncol. 25, 4508–4509 (2007).

    Google Scholar 

  39. Vervenne, W. et al. A randomized, double-blind, placebo (P) controlled, multicenter phase III trial to evaluate the efficacy and safety of adding bevacizumab (B) to erlotinib (E) and gemcitabine (G) in patients (pts) with metastatic pancreatic cancer. J. Clin. Oncol. 26, 4507–4509 (2008).

    Google Scholar 

  40. Wallace, J. A. et al. Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium [Abstract]. J. Clin. Oncol. 25, 4608 (2007).

    Google Scholar 

  41. Spano, J. P. et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 371, 2101–2108 (2008).

    CAS  PubMed  Google Scholar 

  42. Friess, H. et al. A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer 6, 285 (2006).

    PubMed  PubMed Central  Google Scholar 

  43. Evans, T. et al. Final results from cohort 1 of a phase II study of volociximab, an anti-α5β1 integrin antibody, in combination with gemcitabine (GEM) in patients (pts) with metastatic pancreatic cancer (MPC) [Abstract]. J. Clin. Oncol. 25, 4549 (2007).

    Google Scholar 

  44. Mita, M. M. et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of E7820—an oral sulfonamide with novel, α-2 integrin mediated antiangiogenic properties: results of a phase I study [Abstract]. J. Clin. Oncol. 23, 3082 (2005).

    Google Scholar 

  45. Bramhall, S. R., Rosemurgy, A., Brown, P. D., Bowry, C. & Buckels, J. A. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J. Clin. Oncol. 19, 3447–3455 (2001).

    CAS  PubMed  Google Scholar 

  46. Bramhall, S. R. et al. 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, 161–167 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Moore, M. 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. 21, 3296–3302 (2003).

    CAS  PubMed  Google Scholar 

  48. Ruggeri, B. A., Huang, L., Wood, M., Cheng, J. Q. & Testa, J. R. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 21, 81–86 (1998).

    CAS  PubMed  Google Scholar 

  49. Schlieman, M. G., Fahy, B. N., Ramsamooj, R., Beckett, L. & Bold, R. J. Incidence, mechanism and prognostic value of activated Akt in pancreas cancer. Br. J. Cancer 89, 2110–2115 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Asano, T. et al. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells. Oncogene 23, 8571–8580 (2004).

    CAS  PubMed  Google Scholar 

  51. Abe, N. et al. Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 60, 3117–3122 (2000).

    CAS  PubMed  Google Scholar 

  52. Liau, S. S. & Whang, E. HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma. Clin. Cancer Res. 14, 1470–1477 (2008).

    PubMed  PubMed Central  Google Scholar 

  53. Liau, S. S., Ashley, S. W. & Whang, E. E. Lentivirus-mediated RNA interference of HMGA1 promotes chemosensitivity to gemcitabine in pancreatic adenocarcinoma. J. Gastrointest. Surg. 10, 1254–1262 (2006).

    PubMed  Google Scholar 

  54. Trapasso, F. et al. Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models. Cancer Gene Ther. 11, 633–641 (2004).

    CAS  PubMed  Google Scholar 

  55. Ito, D. et al. In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int. J. Cancer 118, 2337–2343 (2006).

    CAS  PubMed  Google Scholar 

  56. Wolpin, B. M. et al. Phase II study of RAD001 in previously treated patients with metastatic pancreatic cancer [Abstract]. J. Clin. Oncol. 26, 4614 (2008).

    Google Scholar 

  57. Azzariti, A., Porcelli, L., Gatti, G., Nicolin, A. & Paradiso, A. Synergic antiproliferative and antiangiogenic effects of EGFR and mTOR inhibitors on pancreatic cancer cells. Biochem. Pharmacol. 75, 1035–1044 (2008).

    CAS  PubMed  Google Scholar 

  58. Tuncyurek, P. et al. Everolimus and mycophenolate mofetil sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard chemotherapy? Eur. Surg. Res. 39, 380–387 (2007).

    CAS  PubMed  Google Scholar 

  59. Rajan, A. et al. mTOR expression in pancreatic adenocarcinoma and its correlation with survival [Abstract]. J. Clin. Oncol. 26, 22169 (2008).

    Google Scholar 

  60. Reuter, S., Eifes, S., Dicato, M., Aggarwal, B. B. & Diederich, M. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem. Pharmacol. 76, 1340–1351 (2008).

    CAS  PubMed  Google Scholar 

  61. Wang, Z. et al. Synergistic effects of multiple natural products in pancreatic cancer cells. Life Sci. 83, 293–300 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sun, M. et al. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol. Cancer Ther. 7, 464–473 (2008).

    CAS  PubMed  Google Scholar 

  63. Dhillon, N. et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14, 4491–4499 (2008).

    CAS  PubMed  Google Scholar 

  64. Epelbaum, R., Vizel, B. & Bar-Sela, G. Phase II study of curcumin and gemcitabine in patients with advanced pancreatic cancer [Abstract]. J. Clin. Oncol. 26, 15619 (2008).

    Google Scholar 

  65. Alberts, S. R. et al. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann. Oncol. 16, 1654–1661 (2005).

    CAS  PubMed  Google Scholar 

  66. Sloss, C. M. et al. Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells. Clin. Cancer Res. 14, 5116–5123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Tucker, O. N. et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 59, 987–990 (1999).

    CAS  PubMed  Google Scholar 

  68. Ding, X. Z., Hennig, R. & Adrian, T. E. Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol. Cancer 2, 10 (2003).

    PubMed  PubMed Central  Google Scholar 

  69. Wei, D. et al. Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 64, 2030–2038 (2004).

    CAS  PubMed  Google Scholar 

  70. Chuang, H. C., Kardosh, A., Gaffney, K. J., Petasis, N. A. & Schonthal, A. H. COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro. Mol. Cancer 7, 38 (2008).

    PubMed  PubMed Central  Google Scholar 

  71. Xiong, H. Q. et al. A phase II trial of gemcitabine and celecoxib for metastatic pancreatic cancer [Abstract]. J. Clin. Oncol. 23, 4174 (2005).

    Google Scholar 

  72. Ferrari, V. et al. Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother. Pharmacol. 57, 185–190 (2006).

    CAS  PubMed  Google Scholar 

  73. Dragovich, T. et al. Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am. J. Clin. Oncol. 31, 157–162 (2008).

    CAS  PubMed  Google Scholar 

  74. Kerr, S. et al. Phase II trial of gemcitabine and irinotecan plus celecoxib in advanced adenocarcinoma of the pancreas [Abstract]. J. Clin. Oncol. 23, 4155 (2005).

    Google Scholar 

  75. Goggins, M. et al. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 58, 5329–5332 (1998).

    CAS  PubMed  Google Scholar 

  76. Levy, L. & Hill, C. S. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial–mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell Biol. 25, 8108–8125 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Melisi, D. et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol. Cancer Ther. 7, 829–840 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Medicherla, S. et al. Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment. Anticancer Res. 27, 4149–4157 (2007).

    CAS  PubMed  Google Scholar 

  79. Hilbig, A. et al. Preliminary results of a phase I/II study in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma using systemic i.v. administration of AP 12009 [Abstract]. J. Clin. Oncol. 26, 4621 (2008).

    Google Scholar 

  80. Furukawa, T., Duguid, W. P., Kobari, M., Matsuno, S. & Tsao, M. S. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am. J. Pathol. 147, 889–895 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Tomioka, D. et al. Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 61, 7518–7524 (2001).

    CAS  PubMed  Google Scholar 

  82. Ogura, Y. et al. Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival. Cancer Gene Ther. 13, 520–529 (2006).

    CAS  PubMed  Google Scholar 

  83. Jin, H. et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res. 68, 4360–4368 (2008).

    CAS  PubMed  Google Scholar 

  84. Garcia, A. et al. Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose [Abstract]. J. Clin. Oncol. 25, 3525 (2007).

    Google Scholar 

  85. Hakam, A., Fang, Q., Karl, R. & Coppola, D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig. Dis. Sci. 48, 1972–1978 (2003).

    CAS  PubMed  Google Scholar 

  86. Adachi, Y. et al. Molecular targeting of IGF-I receptor for human pancreatic cancer [Abstract]. J. Clin. Oncol. 25, 14051 (2007).

    Google Scholar 

  87. Piao, W. et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol. Cancer Ther. 7, 1483–1493 (2008).

    CAS  PubMed  Google Scholar 

  88. Shen, Y. M., Yang, X. C., Yang, C. & Shen, J. K. Enhanced therapeutic effects for human pancreatic cancer by application of K-ras and IGF-IR antisense oligodeoxynucleotides. World J. Gastroenterol. 14, 5176–5185 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Beltran, P. J. et al. Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models. J. Clin. Oncol. 26, 4617–4625 (2008).

    Google Scholar 

  90. Prewett, M. et al. IMC-A12 enhances the efficacy of cetuximab + gemcitabine therapy in human pancreatic carcinoma xenografts in AACR Meeting Abstracts 2007 652 (The American Association for Cancer Research, Philadelphia, 2007).

    Google Scholar 

  91. Furuyama, K. et al. Clinical significance of focal adhesion kinase in resectable pancreatic cancer. World J. Surg. 30, 219–226 (2006).

    PubMed  Google Scholar 

  92. Liu, W. et al. FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis 29, 1096–1107 (2008).

    PubMed  PubMed Central  Google Scholar 

  93. Hatakeyama, S. et al. Anti-cancer activity of NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, against pancreatic carcinoma [Abstract]. J. Clin. Oncol. 24, 13162 (2006).

    Google Scholar 

  94. Ischenko, I. et al. Effect of Src kinase inhibition on metastasis and tumor angiogenesis in human pancreatic cancer. Angiogenesis 10, 167–182 (2007).

    CAS  PubMed  Google Scholar 

  95. Baker, C. H. et al. Inhibition of PDGFR phosphorylation and Src and Akt activity by GN963 leads to therapy of human pancreatic cancer growing orthotopically in nude mice. Int. J. Oncol. 29, 125–138 (2006).

    CAS  PubMed  Google Scholar 

  96. Trevino, J. G. et al. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am. J. Pathol. 168, 962–972 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kayed, H. et al. Indian hedgehog signaling pathway: expression and regulation in pancreatic cancer. Int. J. Cancer 110, 668–676 (2004).

    CAS  PubMed  Google Scholar 

  99. Berman, D. M. et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003).

    CAS  PubMed  Google Scholar 

  100. Shafaee, Z., Schmidt, H., Du, W., Posner, M. & Weichselbaum, R. Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells. Cancer Chemother. Pharmacol. 58, 765–770 (2006).

    CAS  PubMed  Google Scholar 

  101. Feldmann, G. et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 67, 2187–2196 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hu, W. G., Liu, T., Xiong, J. X. & Wang, C. Y. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells. Acta Pharmacol. Sin. 28, 1224–1230 (2007).

    CAS  PubMed  Google Scholar 

  103. Chang, D. Z. Synthetic miRNAs targeting the GLI-1 transcription factor inhibit division and induce apoptosis in pancreatic tumor cells in AACR Meeting Abstracts 2007 639b (The American Association for Cancer Research, Philadelphia, 2006).

    Google Scholar 

  104. Wang, Z. et al. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol. Cancer Ther. 5, 483–493 (2006).

    CAS  PubMed  Google Scholar 

  105. Wang, Z., Zhang, Y., Banerjee, S., Li, Y. & Sarkar, F. H. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106, 2503–2513 (2006).

    CAS  PubMed  Google Scholar 

  106. Dang, T., Vo, K., Washington, K. & Berlin, J. The role of Notch3 signaling pathway in pancreatic cancer [Abstract]. J. Clin. Oncol. 25, 21049 (2007).

    Google Scholar 

  107. Doucas, H. et al. Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J. Surg. Oncol. 97, 63–68 (2008).

    PubMed  Google Scholar 

  108. Zeng, G. et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8, 279–289 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Pasca di Magliano, M. et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE 2, e1155 (2007).

    PubMed  PubMed Central  Google Scholar 

  110. Nawroth, R. et al. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS ONE 2, e392 (2007).

    PubMed  PubMed Central  Google Scholar 

  111. Romero, D., Iglesias, M., Vary, C. P. & Quintanilla, M. Functional blockade of Smad4 leads to a decrease in beta-catenin levels and signaling activity in human pancreatic carcinoma cells. Carcinogenesis 29, 1070–1076 (2008).

    CAS  PubMed  Google Scholar 

  112. Wang, Z. et al. Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway. Br. J. Cancer 99, 1695–1703 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

    CAS  PubMed  Google Scholar 

  114. Hiyama, E. et al. Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res. 57, 326–331 (1997).

    CAS  PubMed  Google Scholar 

  115. Bernhardt, S. L. et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br. J. Cancer 95, 1474–1482 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Choudhury, A. et al. Treatment of advanced pancreatic cancer patients with a telomerase-peptide vaccine together with gemcitabine: a phase II clinical study in AACR Meeting Abstracts 2007 1863 (The American Association for Cancer Research, Philadelphia, 2007).

    Google Scholar 

  117. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866 (2006).

    CAS  PubMed  Google Scholar 

  118. Tong, A. W. & Nemunaitis, J. Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Ther. 15, 341–355 (2008).

    CAS  PubMed  Google Scholar 

  119. Lee, E. J. et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int. J. Cancer 120, 1046–1054 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Lee, C. J., Dosch, J. & Simeone, D. M. Pancreatic cancer stem cells. J. Clin. Oncol. 26, 2806–2812 (2008).

    PubMed  Google Scholar 

  121. Olive, K. P. & Tuveson, D. A. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin. Cancer Res. 12, 5277–5287 (2006).

    CAS  PubMed  Google Scholar 

  122. Lev-Ari, S. et al. Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells. Biomed. Pharmacother. 59 (Suppl. 2), S276–S280 (2005).

    CAS  PubMed  Google Scholar 

  123. Kunnumakkara, A. B. 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-κB-regulated gene products. Cancer Res. 67, 3853–3861 (2007).

    CAS  PubMed  Google Scholar 

  124. El-Rayes, B. F., Ali, S., Sarkar, F. H. & Philip, P. A. Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines. Mol. Cancer Ther. 3, 1421–1426 (2004).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Centre for Molecular Oncology and Imaging, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Han H. Wong

  2. Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Nicholas R. Lemoine

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  1. Han H. Wong
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Correspondence to Nicholas R. Lemoine.

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Wong, H., Lemoine, N. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 6, 412–422 (2009). https://doi.org/10.1038/nrgastro.2009.89

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