Pancreatic Cancer pp 1319-1335 | Cite as

Emerging Therapeutic Targets for Pancreatic Cancer

  • Rachna T. Shroff
  • James L. Abbruzzese
Reference work entry


Pancreatic cancer remains a leading cause of cancer mortality in the United States, however a number of novel molecular targets have emerged that offer promising new therapeutic options for this deadly disease. For instance, inhibition of various transcription factors has demonstrated therapeutic potential in preclinical studies. The transcription factors discussed include nuclear factor kappa B, transforming growth factor β, specificity protein 1, and Gli1. Another important area of research involves preventing the phenotypic switch known as the epithelial-to-mesenchymal transition (EMT) that affects the invasive potential of cancer cells. Targeting the hepatocyte growth factor and its receptor c-Met may reverse EMT and also results in decreased pancreatic cancer growth and may provide a means to reverse chemoresistance to gemcitabine. Furthermore, the DNA repair pathway involves various genes including BRCA2 that are involved in homologous recombination, and CHEK-1/2, a cell cycle checkpoint kinase, both of which provide opportunities for individualizing pancreatic cancer treatment in patients with alterations in these pathways. Preclinical data have shown that BRCA2 mutants are more sensitive to traditional cytotoxic agents, including cisplatin, while specific polymorphisms in CHEK-1, as an example, strengthen gemcitabine’s utility as a radiosensitizer in patients with locally-advanced pancreatic cancer. Also of interest, the proteasome inhibitor bortezomib causes endoplasmic reticulum stress in vitro and in vivo, thereby activating apoptosis in pancreatic cancer cells. Finally, advances in gene therapy will be discussed as this provides a mechanism for targeting pancreatic cancer cells with potentially few side effects.


Vascular Endothelial Growth Factor Pancreatic Cancer Endoplasmic Reticulum Stress Hepatocyte Growth Factor Pancreatic Cancer Cell 
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.


  1. 1.
    Moore MJ, Goldstein D, Hamm 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 2007;25:1960–1966.CrossRefPubMedGoogle Scholar
  2. 2.
    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;23:8033–8040.CrossRefPubMedGoogle Scholar
  3. 3.
    Van Cutsem E, Karasek P, Oettle H, et al.: Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine plus placebo in advanced pancreatic cancer (PC). In American Society of Clinical Oncology Annual Meeting 2002, Orlando, May 18–21, 2002. Alexandria: American Society of Clinical Oncology, 2002. Abstr 517.Google Scholar
  4. 4.
    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;21:3296–3302.CrossRefPubMedGoogle Scholar
  5. 5.
    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. In ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;2518(Suppl.):LBA4509.Google Scholar
  6. 6.
    Wang W, Abbruzzese JL, Evans DB, et al.: The nuclear factor-κB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999;5:119–127.PubMedGoogle Scholar
  7. 7.
    Arlt A, Gehrz A, Muerkoster S, et al.: Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 2003;22:3243–3251.CrossRefPubMedGoogle Scholar
  8. 8.
    Li Y, Ellis KL, Ali S, et al.: Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappa B in BxPC-3 pancreatic cancer cell line. Pancreas 2004;28:e90–e95.CrossRefPubMedGoogle Scholar
  9. 9.
    Sclabas GM, Uwagawa T, Schmidt C, et al.: Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 2005;103:2485–2490.CrossRefPubMedGoogle Scholar
  10. 10.
    Uwagawa T, Li Z, Chang Z, et al.: Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer 2007;109:2142–2153.CrossRefPubMedGoogle Scholar
  11. 11.
    Xie K, Wei D, Huang S: Transcriptional anti-angiogenesis therapy of human pancreatic cancer. Cytokine Growth Factor Rev 2006;17:147–156.CrossRefPubMedGoogle Scholar
  12. 12.
    Shi Q, Le X, Abbruzzese JL, et al.: Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 2001;61:4143–4154.PubMedGoogle Scholar
  13. 13.
    Xie K, Wei D, Shi Q, et al.: Constitutive and inducible expression and regulation of vascular endothelial growth factor. Cytokine Growth Factor Rev 2004;15:297–324.CrossRefPubMedGoogle Scholar
  14. 14.
    Wei D, Wang L, He Y, 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 2004;64:2030–2038.CrossRefPubMedGoogle Scholar
  15. 15.
    Abdelrahim M, Baker CH, Abbruzzese JL, et al.: Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst 2006;98:855–868.CrossRefPubMedGoogle Scholar
  16. 16.
    Yuan P, Wang L, Wei D, et al.: Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer 2007;110:2682–2690.CrossRefPubMedGoogle Scholar
  17. 17.
    Abdelrahim M, Baker CH, Abbruzzese JL, et al.: Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Cancer Res 2007;67:3286–3294.CrossRefPubMedGoogle Scholar
  18. 18.
    Blobe GC, Schiemann WP, Lodish HF: Role of transforming growth factor beta in human disease. N Engl J Med 2000;342:1350–1358.CrossRefPubMedGoogle Scholar
  19. 19.
    Derynck R, Zhang YE: Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003;425:577–584.CrossRefPubMedGoogle Scholar
  20. 20.
    Moustakas A, Heldin CH: Non-Smad TGF-β signals. J Cell Sci 2005;118:3573–3584.CrossRefPubMedGoogle Scholar
  21. 21.
    Levy L, Hill CS: Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 2006;17:41–58.CrossRefPubMedGoogle Scholar
  22. 22.
    Lee JM, Dedhar S, Kalluri R, et al.: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006;172:973–981.CrossRefPubMedGoogle Scholar
  23. 23.
    Culhaci N, Sagol O, Karademir S, et al.: Expression of transforming growth factor-β-1 and p27Kip1 in pancreatic adenocarcinomas: relation with cell-cycle-associated proteins and clinicopathologic characteristics. BMC Cancer 2005;5:98.CrossRefPubMedGoogle Scholar
  24. 24.
    Teraoka H, Sawada T, Yamashita Y, et al.: TGF-β1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion. Int J Oncol 2001;19:709–715.PubMedGoogle Scholar
  25. 25.
    Friess H, Yamanaka Y, Buchler M, et al.: Enhanced expression of transforming growth factor β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846–1856.PubMedGoogle Scholar
  26. 26.
    Wagner M, Kleeff J, Friess H, et al.: Enhanced expression of the type II transforming growth factor-β receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999;19:370–376.CrossRefPubMedGoogle Scholar
  27. 27.
    Bierie B, Moses HL: TGF-β and cancer. Cytokine Growth Factor Rev 2006;17:29–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Yen TW, Aardal NP, Bronner MP, et al.: Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. Surgery 2002;131:129–134.CrossRefPubMedGoogle Scholar
  29. 29.
    Melisi D, Ishiyama S, Sclabas GM, et al.: LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008;7:829–840.CrossRefPubMedGoogle Scholar
  30. 30.
    Feldmann G, Fendrich V, McGovern K, et al.: An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther 2008;7:2725–2735.CrossRefPubMedGoogle Scholar
  31. 31.
    Feldmann G, Dhara S, Fendrich V, et al.: Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67:2187–2196.CrossRefPubMedGoogle Scholar
  32. 32.
    Li C, Heidt DG, Dalerba P, et al.: Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–1037.CrossRefPubMedGoogle Scholar
  33. 33.
    Natalwala A, Spychal R, Tselepis C: Epithelial-mesenchymal transition mediated tumourigenesis in the gastrointestinal tract. World J Gastroenterol 2008;14:3792–3797.CrossRefPubMedGoogle Scholar
  34. 34.
    Lowy AM, Knight J, Groden J: Restoration of E-cadherin/beta-catenin expression in pancreatic cancer cells inhibits growth by induction of apoptosis. Surgery 2002;132:141–148.CrossRefPubMedGoogle Scholar
  35. 35.
    Hotz B, Arndt M, Dullat S, et al.: Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res 2007;13:4769–4776.CrossRefPubMedGoogle Scholar
  36. 36.
    Burk U, Schubert J, Wellner U, et al.: A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2008;9:582–589.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhou BP, Hung MC: Wnt, hedgehog and snail: sister pathways that control by GSK-3ß and ß-Trcp in the regulation of metastasis. Cell Cycle 2005;4:772–776.CrossRefPubMedGoogle Scholar
  38. 38.
    Feldmann G, Dhara S, Fendrich V, et al.: Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67:2187–2196.CrossRefPubMedGoogle Scholar
  39. 39.
    Jeffers M, Rong S, Vande Woude GF: Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol Cell Biol 1996;16:1115–1125.PubMedGoogle Scholar
  40. 40.
    Jiang W, Hiscox S, Matsumoto K, et al.: Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Crit Rev Oncol Hematol 1999;29:209–248.CrossRefPubMedGoogle Scholar
  41. 41.
    Christensen JG, Burrows J, Salgia R: c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett 2005;225:1–26.CrossRefPubMedGoogle Scholar
  42. 42.
    Tomioka D, Maehara N, Kuba K, et al.: Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res 2001;61:7518–7524.PubMedGoogle Scholar
  43. 43.
    Ebert M, Yokoyama M, Friess H, Buchler MW, Korc M: Coexpression of the c-met proto-oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res 1994;54:5775–5778.PubMedGoogle Scholar
  44. 44.
    Vila MR, Nakamura T, Real FX: Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro. Lab Invest 1995;73:409–418.PubMedGoogle Scholar
  45. 45.
    Maehara N, Matsumoto K, Kuba K, Mizumoto K, Tanaka M, Nakamura T: NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer. Br J Cancer 2001;84:864–873.CrossRefPubMedGoogle Scholar
  46. 46.
    Ogura Y, Mizumoto K, Nagai E, 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 2006;13:520–529.CrossRefPubMedGoogle Scholar
  47. 47.
    Miyazawa K, Shimomura T, Kitamura N: Activation of hepatocyte growth factor in the injured tissues is mediated by hepatocyte growth factor activator. J Biol Chem 1996;271:3615–3618.PubMedGoogle Scholar
  48. 48.
    Kitajima Y, Ide T, Ohtsuka T, et al.: Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c-Met system via hypoxia inducible factor-1 in pancreatic cancer. Cancer Sci 2008;99:1341–1347.CrossRefPubMedGoogle Scholar
  49. 49.
    Kim KJ, Wang L, Su YC, et al.: Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts. Clin Cancer Res 2006;12:1292–1298.CrossRefPubMedGoogle Scholar
  50. 50.
    Jin H, Yang R, Zheng Z, et al.: MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res 2008;68:4360–4368.CrossRefPubMedGoogle Scholar
  51. 51.
    Shah AN, Summy JM, Zhang J, et al.: Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 2007;14:3629–3637.CrossRefPubMedGoogle Scholar
  52. 52.
    Hahn SA, Greenhalf B, Ellis I, et al.: BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003;95:214–221.CrossRefPubMedGoogle Scholar
  53. 53.
    Powell SN, Kachnic LA: Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 2003;22:5784–5791.CrossRefPubMedGoogle Scholar
  54. 54.
    Martin RW, Connell PP, Bishop DK: The Yin and Yang of treating BRCA-deficient tumors. Cell 2008;132:919–920.CrossRefPubMedGoogle Scholar
  55. 55.
    Chen PL, Chen CF, Chen Y, et al.: The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci USA 1998;95:5287–5292.CrossRefPubMedGoogle Scholar
  56. 56.
    Goggins M, Schutte M, Lu J, et al.: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996;56:5360–5364.PubMedGoogle Scholar
  57. 57.
    Yuan SS, Lee SY, Chen G, et al.: BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 1999;59:3547–3551.PubMedGoogle Scholar
  58. 58.
    Tutt A, Bertwistle D, Valentine J, et al.: Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J 2001;20:4704–4716.CrossRefPubMedGoogle Scholar
  59. 59.
    Helleday T, Bryant HE, Schultz N: Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 2005;4:1176–1178.CrossRefPubMedGoogle Scholar
  60. 60.
    de Murcia JM, Niedergang C, Trucco C, et al.: Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci USA 1997;94:7303–7307.CrossRefPubMedGoogle Scholar
  61. 61.
    Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917–921.CrossRefPubMedGoogle Scholar
  62. 62.
    Bryant HE, Schultz N, Thomas HD, et al.: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913–917.CrossRefPubMedGoogle Scholar
  63. 63.
    Karnitz LM, Flatten KS, Wagner JM, et al.: Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol 2005;68:1636–1644.PubMedGoogle Scholar
  64. 64.
    Shi Z, Azuma A, Sampath D, et al.: S-Phase arrest by nucleoside analogues and abrogation of survival without cell cycle progression by 7-hydroxystaurosporine. Cancer Res 2001;61:1065–1072.PubMedGoogle Scholar
  65. 65.
    Morgan MA, Parsels LA, Parsels JD, et al.: Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. Cancer Res 2005;65:6835–6842.CrossRefPubMedGoogle Scholar
  66. 66.
    Matthews DJ, Yakes FM, Chen J, et al.: Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 2007;6:104–110.PubMedGoogle Scholar
  67. 67.
    Okazaki T, Jiao L, Chang P, et al.: Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer. Clin Cancer Res 2008;14:2042–2048.CrossRefPubMedGoogle Scholar
  68. 68.
    Rao RV, Hermel E, Castro-Obregon S, et al.: Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem 2001;276:33869–33874.CrossRefPubMedGoogle Scholar
  69. 69.
    Nawrocki ST, Bruns CJ, Harbison MT, et al.: Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 2002;1:1243–1253.PubMedGoogle Scholar
  70. 70.
    Nawrocki ST, Carew JS, Pino MS, et al.: Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res 2005;65:11658–11666.CrossRefPubMedGoogle Scholar
  71. 71.
    Nawrocki ST, Sweeney-Gotsch B, Takamori R, et al.: The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 2004;12:59–70.Google Scholar
  72. 72.
    Nawrocki ST, Carew JS, Pino MS, et al.: Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006;66:3773–3781.CrossRefPubMedGoogle Scholar
  73. 73.
    Wen Y, Yan DH, Wang B, et al.: p202, an interferon-inducible protein, mediates multiple antitumor activities in human pancreatic cancer xenograft models. Cancer Res 2001;61:7142–7147.PubMedGoogle Scholar
  74. 74.
    Li Z, Ding Q, Li Y, et al.: Suppression of pancreatic tumor progression by systemic delivery of a pancreatic-cancer-specific promoter driven Bik mutant. Cancer Lett 2006;236:58–63.CrossRefPubMedGoogle Scholar
  75. 75.
    Li YM, Wen Y, Zhou BP, et al.: Enhancement of bik antitumor effect by bik mutants. Cancer Res 2003;63:7630–7633.PubMedGoogle Scholar
  76. 76.
    Xie X, Xia W, Li Z, et al.: Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models. Cancer Cell 2007;12:52–65.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Rachna T. Shroff
    • 1
  • James L. Abbruzzese
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyUniversity of Texas, M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations