Seminars in Oncology
Volume 34, Issue 4 , Pages 354-364 , August 2007

Future Strategies for Targeted Therapies and Tailored Patient Management in Pancreatic Cancer

  • Andrew H. Ko

      Affiliations

    • Corresponding Author InformationAddress correspondence to Andrew H. Ko, MD, 1600 Divisadero Street, 4th floor, Box 1705, San Francisco, CA 94115.

References 

  1. 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
  2. O’Reilly E, Abou-Alfa G, Letourneau R, et al. A randomized phase III trial of DX-8951f (Exatecan Mesylate; DX) and gemcitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer. Proc Am Soc Clin Oncol. 2004;23:314;(abstr 4006)
  3. Louvet C, Labianca R, Hammel P, et al. Gemcitabine versus GEMOX (gemcitabine + oxaliplatin) in nonresectable pancreatic adenocarcinoma: Interim results of the GERCOR/GISCAD Intergroup phase III. Proc Am Soc Clin Oncol. 2003;22:250;(abstr 1004)
  4. Heinemann V, Quietzsch D, Gieseler F, et al. A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreatic carcinoma. Proc Am Soc Clin Oncol. 2003;22:250;(abstr 1003)
  5. Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270–3275
  6. Cunningham D, Chau I, Stocken D, et al: Phase III randomised comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. ECCO 13—The European Cancer Conference, Paris, France, Oct 30-Nov 3, 2005 (abstr PS11)
  7. Maloney D. Monoclonal antibodies. In:  Liotta L editors. The Molecular Basis of Cancer. Philadelphia, PA: Saunders; 2001;p. 467–501
  8. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol. 2003;21:2787–2799
  9. Bosslet K, Kern HF, Kanzy EJ, et al. A monoclonal antibody with binding and inhibiting activity towards human pancreatic carcinoma cells (I. Immunohistological and immunochemical characterization of a murine monoclonal antibody selecting for well differentiated adenocarcinomas of the pancreas). Cancer Immunol Immunother. 1986;23:185–191
  10. Buchler M, Friess H, Malfertheiner P, et al. Studies of pancreatic cancer utilizing monoclonal antibodies. Int J Pancreatol. 1990;7:151–157
  11. Buchler M, Friess H, Schultheiss KH, et al. A randomized controlled trial of adjuvant immunotherapy (murine monoclonal antibody 494/32) in resectable pancreatic cancer. Cancer. 1991;68:1507–1512
  12. Buchler M, Kubel R, Malfertheiner P, et al. [Immunotherapy of advanced pancreatic carcinoma with the monoclonal antibody BW 494]. Dtsch Med Wochenschr. 1988;113:374–380
  13. Schulz G, Buchler M, Muhrer KH, et al. Immunotherapy of pancreatic cancer with monoclonal antibody BW 494. Int J Cancer. 1988;2(suppl):89–94
  14. Gottlinger HG, Funke I, Johnson JP, et al. The epithelial cell surface antigen 17-1A, a target for antibody-mediated tumor therapy: Its biochemical nature, tissue distribution and recognition by different monoclonal antibodies. Int J Cancer. 1986;38:47–53
  15. Weiner LM, Harvey E, Padavic-Shaller K, et al. Phase II multicenter evaluation of prolonged murine monoclonal antibody 17-1A therapy in pancreatic carcinoma. J Immunother. 1993;13:110–116
  16. Hall PA, Hughes CM, Staddon SL, et al. The c-erb B-2 proto-oncogene in human pancreatic cancer. J Pathol. 1990;161:195–200
  17. Satoh K, Sasano H, Shimosegawa T, et al. An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer. 1993;72:51–56
  18. Yamanaka Y, Friess H, Kobrin MS, et al. Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol. 1993;24:1127–1134
  19. Lei S, Appert HE, Nakata B, et al. Overexpression of HER2/neu oncogene in pancreatic cancer correlates with shortened survival. Int J Pancreatol. 1995;17:15–21
  20. Day JD, Digiuseppe JA, Yeo C, et al. Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol. 1996;27:119–124
  21. Novotny J, Petruzelka L, Vedralova J, et al. Prognostic significance of c-erbB-2 gene expression in pancreatic cancer patients. Neoplasma. 2001;48:188–191
  22. Safran H, Steinhoff M, Mangray S, et al. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol. 2001;24:496–499
  23. Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. 2004;22:706–712
  24. Jones L, Ghaneh P, Humphreys M, et al. The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer. Ann N Y Acad Sci. 1999;880:288–307
  25. 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;182:347–355
  26. 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
  27. Bramhall SR, Schulz J, Nemunaitis J, 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. 2002;87:161–167
  28. 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
  29. Grunewald K, Lyons J, Frohlich A, et al. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer. 1989;43:1037–1041
  30. End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 2001;61:131–137
  31. 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;23:485–487
  32. 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;22:1430–1438
  33. Wells A. EGF receptor. Int J Biochem Cell Biol. 1999;31:637–643
  34. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin Cancer Res. 2001;7:2958–2970
  35. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–137
  36. Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: Receptor heterodimerization in development and cancer. Embo J. 2000;19:3159–3167
  37. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–225
  38. Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997;410:83–86
  39. Goldman CK, Kim J, Wong WL, et al. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: A model of glioblastoma multiforme pathophysiology. Mol Biol Cell. 1993;4:121–133
  40. Schreiber AB, Winkler ME, Derynck R. Transforming growth factor-alpha: A more potent angiogenic mediator than epidermal growth factor. Science. 1986;232:1250–1253
  41. Montz R, Klapdor R, Rothe B, et al. Immunoscintigraphy and radioimmunotherapy in patients with pancreatic carcinoma. Nuklearmedizin. 1986;25:239–244
  42. Aaronson SA. Growth factors and cancer. Science. 1991;254:1146–1153
  43. Grandis JR, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90:824–832
  44. Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol. 2000;21:105–115
  45. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 1999;82:241–250
  46. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232
  47. Downward J, Yarden Y, Mayes E, et al. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984;307:521–527
  48. Sandgren EP, Luetteke NC, Palmiter RD, et al. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990;61:1121–1135
  49. Xu YH, Richert N, Ito S, et al. Characterization of epidermal growth factor receptor gene expression in malignant and normal human cell lines. Proc Natl Acad Sci U S A. 1984;81:7308–7312
  50. Di Fiore PP, Pierce JH, Fleming TP, et al. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987;51:1063–1070
  51. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: Current knowledge and future directions. J Clin Oncol. 2005;23:2556–2568
  52. Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A. 1994;91:7727–7731
  53. Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995;55:5536–5539
  54. Moscatello DK, Holgado-Madruga M, Emlet DR, et al. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem. 1998;273:200–206
  55. Barton CM, Hall PA, Hughes CM, et al. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol. 1991;163:111–116
  56. 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;13:565–569
  57. Tobita K, Kijima H, Dowaki S, et al. Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int J Mol Med. 2003;11:305–309
  58. Murphy LO, Cluck MW, Lovas S, et al. Pancreatic cancer cells require an EGF receptor-mediated autocrine pathway for proliferation in serum-free conditions. Br J Cancer. 2001;84:926–935
  59. Xiong HQ, Abbruzzese JL. Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Semin Oncol. 2002;29:31–37
  60. Ciardiello F, Caputo R, Bianco R, et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6:2053–2063
  61. Sirotnak FM, Zakowski MF, Miller VA, et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2000;6:4885–4892
  62. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23:1803–1810
  63. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–1208
  64. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568–5577
  65. Overholser JP, Prewett MC, Hooper AT, et al. Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer. 2000;89:74–82
  66. Buchsbaum DJ, Bonner JA, Grizzle WE, et al. Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys. 2002;54:1180–1193
  67. 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
  68. 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;22:2610–2616
  69. Philip PA, Benedetti J, Fenoglio-Preiser C, et al. Phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma. (SWOG S02025 study) J Clin Oncol. 2007;25:965s;(suppl 18, abstr LBA4059)
  70. Kim TE, Murren JR. Erlotinib OSI/Roche/Genentech. Curr Opin Investig Drugs. 2002;3:1385–1395
  71. Grunwald V, Hidalgo M. Development of the epidermal growth factor receptor inhibitor OSI-774. Semin Oncol. 2003;30:23–31
  72. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–132
  73. Ng SS, Tsao MS, Nicklee T, et al. Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Ther. 2002;1:777–783
  74. Solorzano CC, Baker CH, Tsan R, et al. Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma. Clin Cancer Res. 2001;7:2563–2572
  75. Baker CH, Solorzano CC, Fidler IJ. Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res. 2002;62:1996–2003
  76. 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
  77. 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
  78. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med. 1971;285:1182–1186
  79. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–1027
  80. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer. 2003;2:8
  81. Luo J, Guo P, Matsuda K, et al. Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo. Int J Cancer. 2001;92:361–369
  82. 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;85:27–34
  83. Niedergethmann M, Hildenbrand R, Wostbrock B, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas. 2002;25:122–129
  84. 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;3:1309–1316
  85. Ikeda N, Adachi M, Taki T, et al. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer. 1999;79:1553–1563
  86. 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;88:2239–2245
  87. Buchler P, Reber HA, Buchler MW, et al. VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg. 2002;236:738–749
  88. Hotz HG, Reber HA, Hotz B, et al. Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth. J Gastrointest Surg. 2001;5:131–138
  89. Tokunaga T, Abe Y, Tsuchida T, et al. Ribozyme mediated cleavage of cell-associated isoform of vascular endothelial growth factor inhibits liver metastasis of a pancreatic cancer cell line. Int J Oncol. 2002;21:1027–1032
  90. Bruns CJ, Shrader M, Harbison MT, et al. Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer. 2002;102:101–108
  91. Hoshida T, Sunamura M, Duda DG, et al. Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor. Pancreas. 2002;25:111–121
  92. Ogawa T, Takayama K, Takakura N, et al. Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor. Cancer Gene Ther. 2002;9:633–640
  93. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med. 2001;7:987–989
  94. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342
  95. Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2006;23:8033–8040
  96. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53:549–554
  97. Hirano T, Shino Y, Saito T, et al. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Oncogene. 2002;21:5923–5928
  98. Ehlers RA, Zhang Y, Hellmich MR, et al. Neurotensin-mediated activation of MAPK pathways and AP-1 binding in the human pancreatic cancer cell line, MIA PaCa-2. Biochem Biophys Res Commun. 2000;269:704–708
  99. Douziech N, Calvo E, Laine J, et al. Activation of MAP kinases in growth responsive pancreatic cancer cells. Cell Signal. 1999;11:591–602
  100. Douziech N, Lajas A, Coulombe Z, et al. Growth effects of regulatory peptides and intracellular signaling routes in human pancreatic cancer cell lines. Endocrine. 1998;9:171–183
  101. Yip-Schneider MT, Lin A, Barnard D, et al. Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. Int J Oncol. 1999;15:271–279
  102. Strumberg D, Schuehly U, Moeller JG, et al. Phase I clinical, pharmacokinetic and pharmacodynamic study of the Raf kinase inhibitor BAY 43-9006 in patients with locally advanced or metastatic cancer. Proc Am Soc Clin Oncol. 2001;20:83a;(abstr 330)
  103. O’Dwyer PJ, Stevenson JP, Gallagher M, et al. c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132. Clin Cancer Res. 1999;5:3977–3982(CGP 69846A)
  104. Stevenson JP, Yao KS, Gallagher M, et al. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132. J Clin Oncol. 1999;17:2227–2236(CGP 69846A)
  105. Tolcher AW, Reyno L, Venner PM, et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2002;8:2530–2535
  106. Cripps MC, Figueredo AT, Oza AM, et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: A National Cancer Institute of Canada Clinical Trials Group study. Clin Cancer Res. 2002;8:2188–2192
  107. Coudert B, Anthoney A, Fiedler W, et al. Phase II trial with ISIS 5132 in patients with small-cell (SCLC) and non-small cell (NSCLC) lung cancer (A European Organization for Research and Treatment of Cancer (EORTC) Early Clinical Studies Group report). Eur J Cancer. 2001;37:2194–2198
  108. LoRusso P, Adjei A, Meyer M, et al. A phase I clinical and pharmacokinetic evaluation of the oral MEK inhibitor, CI-1040, administered for 21 consecutive days, repeated every 4 weeks in patients with advanced cancer. Proc Am Soc Clin Oncol. 2002;21:81a;(abstr 321)
  109. Mitchell D, Reid J, Parchment R, et al. Pharmacokinetics and pharmacodynamics of the oral MEK inhibitor, CI-1040, following multiple dose administration to patients with advanced cancer. Proc Am Soc Clin Oncol. 2002;21:81a;(abstr 320)
  110. Waterhouse D, Rinehwart J, Adjei A, et al. A phase 2 study of an oral MEK inhibitor, CI-1040, in patients with advanced nonsmall-cell lung, breast, colon, or pancreatic cancer. Proc Am Soc Clin Oncol. 2003;22:204;(abstr 816)
  111. Wallace JA, Locker G, Nattam S, et al: Sorafenib plus gemcitabine for advanced pancreatic cancer: A phase II trial of the University of Chicago phase II consortium. 2007 Gastrointestinal Cancers Symposium, Orlando, FL, Jan 19-21, 2007 (abstr 106)
  112. Shah SA, Potter MW, McDade TP, et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem. 2001;82:110–122
  113. Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res. 2001;100:11–17
  114. 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
  115. Alberts SR, Foster NR, Morton RF, 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. 2005;16:1654–1661
  116. Brett BT, Smith SC, Bouvier CV, et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol. 2002;20:4225–4231
  117. Shapiro J, Marshall J, Karasek P, et al. G17DT+gemcitabine 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. Proc Am Soc Clin Oncol. 2005;23:310s;(abstr 4012)
  118. Jaffee EM, Hruban RH, Biedrzycki B, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: A phase I trial of safety and immune activation. J Clin Oncol. 2001;19:145–156
  119. Laheru D, Yeo C, Biedrzycki B, et al: A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas. 2007 Gastrointestinal Cancers Symposium, Orlando, FL, Jan 19-21, 2007 (abstr 106)
  120. Friess H, Berberat P, Schilling M, et al. Pancreatic cancer: The potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996;74:35–42
  121. Thayer SP, Di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851–856
  122. Hassan R, Laszik Z, Lerner MR, et al. Mesothelin, a cell surface glycoprotein, as a target for tumor specific therapy of pancreatic cancer. Proc Am Soc Clin Oncol. 2003;22:283;(abstr 1138)
  123. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511
  124. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937–1947
  125. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009
  126. Chang JC, Wooten EC, Tsimelzon A, et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet. 2003;362:362–369
  127. Ko A, Scott J, Tempero MA, et al: Detection of circulating micrometastases by flow cytometry in patients with pancreatic carcinoma. Lustgarten Pancreatic Cancer conference, San Francisco, CA, Jun 25-26, 2004 (abstr 50)

PII: S0093-7754(07)00097-8

doi: 10.1053/j.seminoncol.2007.05.002

Seminars in Oncology
Volume 34, Issue 4 , Pages 354-364 , August 2007

Article Tools