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Current Gastroenterology Reports

, Volume 6, Issue 2, pp 119–125 | Cite as

Novel therapies for pancreatic adenocarcinoma

  • Simona M. Pino
  • Henry Q. Xiong
  • David McConkey
  • James L. Abbruzzese
Article

Abstract

Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. In this article we review the current status of investigations into several classes of agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The scientific rationale, mechanism of action, and clinical trial data for these novel agents are discussed.

Keywords

Epidermal Growth Factor Receptor Gemcitabine Celecoxib Pancreatic Adenocarcinoma Epidermal Growth Factor Receptor Expression 
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.

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References and Recommended Reading

  1. 1.
    Jemal A, Murray T, Samuels A: Cancer statistics, 2003. CA Cancer J Clin 2003, 53(Suppl 1):5–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Neoptolemos JP, Dunn JA, Stocken DD, et al.: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomized controlled trial. Lancet 2001, 358:1576–1585.PubMedCrossRefGoogle Scholar
  3. 3.
    Abrams RA, Lillemoe KD, Plantadosi S: Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet 2001, 358:1565–1566.PubMedCrossRefGoogle Scholar
  4. 4.
    Burris HA, 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, 15:2403–2413. This trial established gemcitabine as the standard treatment for advanced pancreatic cancer. The study used clinical benefit response as its primary objective.PubMedGoogle Scholar
  5. 5.
    Von Hoff D, Mahadevan D, Bearss D: New developments in the treatment of patients with pancreatic cancer. Clin Oncol Updates 2001, 4:1–15.Google Scholar
  6. 6.
    Lohr M, Trautmann B, Gottler M, et al.: Human ductal adenocarcinomas of the pancreas express extracellular matrix proteins. Br J Cancer 1994, 69:144–151.PubMedGoogle Scholar
  7. 7.
    Sato H, Takino T, Okada Y, et al.: A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 1994, 370:61–65.PubMedCrossRefGoogle Scholar
  8. 8.
    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, 19:3447–3455. This definitive trial proved that marimastat was not effective for treatment of pancreatic cancer.PubMedGoogle Scholar
  9. 9.
    Bramhall SR, Schulz J, Nemunaitis J, et al.: A double-blind placebo-controlled, randomized study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002, 87(Suppl 2):61–167.Google Scholar
  10. 10.
    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. This trial demonstrated that the addition of gemcitabine to the matrix metalloproteinase inhibitor BAY 12-9566 did not improve survival in patients with advanced pancreatic cancer.PubMedCrossRefGoogle Scholar
  11. 11.
    Hess KR, Abbruzzese JL: Matrix metalloproteinase inhibition of pancreatic cancer: matching mechanism of action to clinical trial design. J Clin Oncol 2001, 19:3445–3446. This commentary provided a critical analysis of the clinical trials for matrix metalloproteinase inhibitors.PubMedGoogle Scholar
  12. 12.
    Hruban RH, Van Mansfeld AD, Offerhaus GJ, et al.: K-ras oncogene activation in adenocarcinoma of the human pancreas: a study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993, 143:545–554.PubMedGoogle Scholar
  13. 13.
    Adjei AA: Blocking oncogenic ras signalling for cancer therapy. J Natl Cancer Inst 2001, 93:1062–1074.PubMedCrossRefGoogle Scholar
  14. 14.
    Casey PJ, Solski PA, Der CJ, et al.: p21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci U S A 1989, 86:8323–8327.PubMedCrossRefGoogle Scholar
  15. 15.
    Lersch C, Van Cutsem E, Amado R, et al.: Randomized phase II study of SCH 66336 and gemcitabine in the treatment of metastatic adenocarcinoma of the pancreas [abstract]. Proc ASCO 2001, 20:608.Google Scholar
  16. 16.
    Macdonald JS, Chansky K, Whitehead R, et al.: A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest Oncology Group (SWOG) [abstract]. Proc ASCO 2002, 21:548.Google Scholar
  17. 17.
    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, 21:1301–1306. This trial demonstrated lack of efficacy of R115777 and provided surrogate marker analysis indicating that Ras was partially inhibited.PubMedCrossRefGoogle Scholar
  18. 18.
    Van Cutsem E, Karasek P, Oettle H, et al.: Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine + placebo in advanced pancreatic cancer (PC) [abstract]. Proc ASCO 2002, 21:517.Google Scholar
  19. 19.
    Arteaga CL: Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol 2002, 29:3–9. A well-written comprehensive review that summarized the biology of EGFR and novel approaches to targeting it.PubMedGoogle Scholar
  20. 20.
    Funatomi H, Itakura J, Ishiwata T, et al.: Amphiregulin antisense oligonucleotide inhibits growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptortargeted therapy. Int J Cancer 1997, 72:512–517.PubMedCrossRefGoogle Scholar
  21. 21.
    Sato JD, Kawamoto T, Le AD, et al.: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983, 1:511–529.PubMedGoogle Scholar
  22. 22.
    Mendelsohn J: Blockade of receptors for growth factors: an anticancer therapy: the fourth annual Joseph H. Burchenal American Association for Cancer Research Clinical Research Award Lecture. Clin Cancer Res 2000, 6:747–753. In this lecture, Mendelsohn summarized the discovery of a monoclonal antibody against EGFR, cetuximab (IMC-C225), as a potential therapy for cancer.PubMedGoogle Scholar
  23. 23.
    Bruns CJ, Harbison MT, Davis DW, et al.: Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000, 6:1936–1948. This study described the mechanism of action of C225.PubMedGoogle Scholar
  24. 24.
    Bruns CJ, Solorzano CC, Harbison MT, et al.: Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000, 60:2926–2935. One of the early publications indicating that the antiangiogenesis property of COX-2 inhibition contributed to the antitumor activity of COX-2 inhibitors.PubMedGoogle Scholar
  25. 25.
    Abbruzzese J, Rosenberg A, Xiong Q, et al.: Phase II study of anti-epidermal growth factor receptor (EGFR) antibody cetuximab (IMC-C225) in combination with gemcitabine in patients with advanced pancreatic cancer [abstract]. Proc ASCO 2001, 20:518.Google Scholar
  26. 26.
    Safran H, Ramanathan RK, Schwartz J, et al.: Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER2/neu [abstract]. Proc ASCO 2001, 20:517.Google Scholar
  27. 27.
    Greenberger LM, Discafani C, Wang YF, et al.: EKB-569: a new irreversible inhibitor of epidermal growth factor receptor tyrosine kinase for the treatment of cancer [abstract]. Clin Cancer Res 2000, 6:4544s.Google Scholar
  28. 28.
    Morgan JA, Bukowski RM, Xiong H, et al.: Preliminary report of a phase 1 study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor (EGFR), given in combination with gemcitabine to patients with advanced pancreatic cancer [abstract]. Proc ASCO 2003, 22:788.Google Scholar
  29. 29.
    Molina MA, Sitja-Arnau M, Lemoine MG, et al.: Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal antiinflammatory drugs. Cancer Res 1999, 59:4356–4362.PubMedGoogle Scholar
  30. 30.
    Yip-Schneider MT, Barnard DS, Billings SD, et al.: Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000, 21:139–146.PubMedCrossRefGoogle Scholar
  31. 31.
    Yip-Schneider MT, Sweeney CJ, Jung SH, et al.: Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther 2001, 298:976–985.PubMedGoogle Scholar
  32. 32.
    Yip-Schneider MT, Wiesenauer CA, Schmidt CM: Inhibition of the phosphatidylinositol 3’-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac. J Gastrointest Surg 2003, 7:354–363.PubMedCrossRefGoogle Scholar
  33. 33.
    Masferrer JL, Leahy KM, Koki AT, et al.: Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000, 60:1306–1311.PubMedGoogle Scholar
  34. 34.
    Leahy KM, Ornberg RL, Wang Y, et al.: Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 2002, 62:625–631.PubMedGoogle Scholar
  35. 35.
    Xiong HQ, Du M, Wolff RA, et al.: Parmacology study of celecoxib in combination with gemcitabine for advanced pancreatic cancer [abstract]. Proc ASCO 2002, 21:448.Google Scholar
  36. 36.
    Smith SE, Burris HA, Loehrer PJ, et al.: Preliminary report of a phase II trial of gemcitabine combined with celecoxib for advanced pancreatic cancer [abstract]. Proc ASCO 2003, 22:1502.Google Scholar
  37. 37.
    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182–1186. The first presentation of the original hypothesis for the dependence of solid tumors on angiogenesis.PubMedCrossRefGoogle Scholar
  38. 38.
    Koong AC, Mehta VK, Le QT, et al.: Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000, 48:919–922.PubMedCrossRefGoogle Scholar
  39. 39.
    Kindler HL, Ansari R, Lester E, et al.: Bevacizumab (B) plus gemcitabine (G) in patients (pts) with advanced pancreatic cancer (PC) [abstract]. Proc ASCO 2003, 22:1037.Google Scholar
  40. 40.
    Chen F, Castranova V, Shi X: New insights into the role of nuclear factor B in cell growth regulation. Am J Pathol 2001, 159:387–397.PubMedGoogle Scholar
  41. 41.
    Wang W, Abbruzzese JL, Evans DB, et al.: The nuclear factor B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999, 59:119–127.Google Scholar
  42. 42.
    Ryan DP, Elder JP, Winkelmann J, et al.: Pharmacokinetic and pharmacodynamic phase I study of PS-341 and gemcitabine in patients with advanced solid tumors [abstract]. Proc ASCO 2002, 21:379.Google Scholar
  43. 43.
    Goeze JP, Nielsen FC, Burcharth F, et al.: Closing the gastrin loop in pancreatic carcinoma: coexpression of gastrin and its receptor in solid human pancreatic adenocarcinoma. Cancer 2000, 88:2487–2494.CrossRefGoogle Scholar
  44. 44.
    Watson SA, Michaeli D, Grimes S, et al.: Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer. Cancer Res 1996, 56:880–885.PubMedGoogle Scholar
  45. 45.
    Gilliam AD, Henwood M, Watson SA, et al.: G17DT therapy may improve the survival of patients with advanced pancreatic carcinoma [abstract]. Proc ASCO 2001, 20:533.Google Scholar
  46. 46.
    Crooke ST: Proof of mechanism of antisense drugs. Antisense Nucleic Acid Drug Dev 1996, 6:145–147.PubMedGoogle Scholar
  47. 47.
    Monia BP, Johnston DJ, Ecker DJ, et al.: Selective inhibition of mutant H-ras mRNA expression by antisense oligonucleotides. J Biol Chem 1992, 267:19954–19962.PubMedGoogle Scholar
  48. 48.
    Chen G, Oh S, Monia BP, et al.: Antisense oligonucleotides demonstrate a dominant role of c-Ki-ras proteins in regulating the proliferation of diploid human fibroblasts. J Biol Chem 1996, 271:28259–28265.PubMedCrossRefGoogle Scholar
  49. 49.
    Burch PA, Alberts SR, Schroeder MT, et al.: Gemcitabine and ISIS-2504 for patients with pancreatic adenocarcinoma (ACA): A North Central Cancer Treatment Group (NCCTG) phase II study [abstract]. Proc ASCO 2003, 22:1038.Google Scholar
  50. 50.
    Hecht JR, Bedford R, Abbruzzese JL, et al.: A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003, 9:555–561.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Simona M. Pino
    • 1
  • Henry Q. Xiong
    • 1
  • David McConkey
    • 1
  • James L. Abbruzzese
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

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