Targeted therapies for pancreatic cancer

British Medical Bulletin

Volumn 87, Issue 1, 2008, Pages 97-130

  Danovi, S A ^a   Wong, H H ^a   Lemoine, N R ^a  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Clinical trials; Novel therapy; Pancreatic cancer; Targeted therapy

Indexed keywords

2 (2 CHLORO 4 IODOANILINO) N CYCLOPROPYLMETHOXY 3,4 DIFLUOROBENZAMIDE; 2 [[2 [[2 [(2 AMINO 3 MERCAPTOPROPYL)AMINO] 3 METHYLPENTYL]OXY] 1 OXO 3 PHENYLPROPYL]AMINO] 4 (METHYLSULFONYL)BUTANOIC ACID ISOPROPYL ESTER; AMG 479; ANTINEOPLASTIC AGENT; AP 12009; BATIMASTAT; BEVACIZUMAB; BORTEZOMIB; CANCER VACCINE; CAPECITABINE; CELECOXIB; CETUXIMAB; CISPLATIN; DOCETAXEL; ERLOTINIB; EVEROLIMUS; FLUOROURACIL; GASTRAZOLE; GEFITINIB; GEMCITABINE; GV 1001; INSEGIA; IRINOTECAN; ISIS 2503; JB 95008; L 778123; MARIMASTAT; MATUZUMAB; OXALIPLATIN; PACLITAXEL; PEMETREXED; PLACEBO; RAPAMYCIN; SC 44463; SORAFENIB; TANOMASTAT; TEMSIROLIMUS; TIPIFARNIB; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABDOMINAL PAIN; ABSENCE OF SIDE EFFECTS; ADD ON THERAPY; ADVANCED CANCER; ANTIANGIOGENIC ACTIVITY; ASTHENIA; BREAST TUMOR; CANCER CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER PALLIATIVE THERAPY; CANCER RADIOTHERAPY; CANCER SURVIVAL; CLINICAL TRIAL; COLORECTAL CANCER; COMBINATION CHEMOTHERAPY; COST EFFECTIVENESS ANALYSIS; DIARRHEA; DRUG MEGADOSE; DRUG TARGETING; DRUG TOLERABILITY; ENZYME INHIBITION; ESOPHAGUS INJURY; GASTROINTESTINAL SYMPTOM; HEART DISEASE; HUMAN; INTESTINE PERFORATION; LOADING DRUG DOSE; LOW DRUG DOSE; LUNG CANCER; MEDICAL INFORMATION; MEDICAL RESEARCH; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; MUSCULOSKELETAL DISEASE; NAUSEA AND VOMITING; NEUTROPENIA; NONHUMAN; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; PHENOTYPE; PRIORITY JOURNAL; RASH; REVIEW; TUMOR VASCULARIZATION; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; HUMANS; PANCREATIC NEOPLASMS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 51749121596     PISSN: 00071420     EISSN: 14718391     Source Type: Journal    
DOI: 10.1093/bmb/ldn027     Document Type: Review

References (209)

1. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet, 363, 1049-1057.
2. Bardeesy N, DePinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer, 2, 897-909.
3. Warshaw AL, Fernandez-del Castillo C (1992) Pancreatic carcinoma. N Engl J Med, 326, 455-465.
4. Burris HA III, Moore MJ, Andersen J et al. (1997) 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.
5. Kleespies A, Jauch KW, Bruns CJ (2006) Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer? Drug Resist Updat, 9, 1-18.
6. Saif MW, Karapanagiotou L, Syrigos K (2007) Genetic alterations in pancreatic cancer. World J Gastroenterol, 13, 4423-4430.
7. Crane CH, Ellis LM, Abbruzzese JL et al. (2006) Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol, 24, 1145-1151.
8. Sledge GW Jr., (2005) What is targeted therapy? J Clin Oncol, 23, 1614-1615.
9. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell, 100, 57-70.
10. Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer, 33, 787-791.
11. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev; 13, 2388-2399.
12. Hiyama E, Kodama T, Shinbara K et al. (1997) Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res, 57, 326-331.
13. Suehara N, Mizumoto K, Muta T et al. (1997) Telomerase elevation in pancreatic ductal carcinoma compared to nonmalignant pathological states. Clin Cancer Res, 3, 993-998.
14. Nguyen B, Elmore LW, Holt SE (2003) Telomerase as a target for cancer immunotherapy. Cancer Biol Ther, 2, 131-136.
15. Forsyth NR, Wright WE, Shay JW (2002) Telomerase and differentiation in multicellular organisms: turn it off, turn it on, and turn it off again. Differentiation, 69, 188-197.
16. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM (1999) The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes. Immunity, 10, 673-679.
17. Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M (2000) Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc Natl Acad Sci USA, 97, 4796-4801.
18. Brunsvig PF, Aamdal S, Gjertsen MK et al. (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother, 55, 1553-1564.
19. Bernhardt SL, Gjertsen MK, Trachsel S et al. (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer, 95, 1474-1482.
20. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev, 18, 4-25.
21. Roy H, Bhardwaj S, Yla-Herttuala S (2006) Biology of vascular endothelial growth factors. FEBS Lett, 580, 2879-2887.
22. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 3, 401-410.
23. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353-364.
24. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer, 2, 795-803.
25. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246, 1306-1309.
26. Plouet J, Schilling J, Gospodarowicz D (1989) Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J, 8, 3801-3806.
27. Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP (1996) Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol, 114, 964-970.
28. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science, 255, 989-991.
29. Terman BI, Dougher-Vermazen M, Carrion ME et al. (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun, 187, 1579-1586.
30. Millauer B, Wizigmann-Voos S, Schnurch H et al. (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell, 72, 835-846.
31. Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA, 90, 7533-7537.
32. Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M (2000) Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer, 85, 27-34.
33. von Marschall Z, Cramer T, Hocker M et al. (2000) De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. Gastroenterology, 119, 1358-1372.
34. Luo J, Guo P, Matsuda K et al. (2001) Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo. Int J Cancer, 92, 361-369.
35. Tsuzuki Y, Mouta Carreira C, Bockhorn M, Xu L, Jain RK, Fukumura D (2001) Pancreas microenvironment promotes VEGF expression and tumor growth: novel window models for pancreatic tumor angiogenesis and microcirculation. Lab Invest, 81, 1439-1451.
36. Solorzano CC, Baker CH, Bruns CJ et al. (2001) Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Cancer Biother Radiopharm, 16, 359-370.
37. Baker CH, Solorzano CC, Fidler IJ (2002) Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res, 62, 1996-2003.
38. Bockhorn M, Tsuzuki Y, Xu L, Frilling A, Broelsch CE, Fukumura D (2003) Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. Clin Cancer Res, 9, 4221-4226.
39. Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW, Korc M (1997) Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res, 3, 1309-1316.
40. Ikeda N, Adachi M, Taki T et al. (1999) Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer, 79, 1553-1563.
41. Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K (2000) 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.
42. Presta LG, Chen H, O'Connor SJ et al. (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res, 57, 4593-4599.
43. Kim KJ, Li B, Houck K, Winer J, Ferrara N (1992) The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors, 7, 53-64.
44. Gordon MS, Margolin K, Talpaz M et al. (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol, 19, 843-850.
45. Margolin K, Gordon MS, Holmgren E et al. (2001) Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol, 19, 851-856.
46. Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med, 350, 2335-2342.
47. Kindler HL, Friberg G, Singh DA et al. (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol, 23, 8033-8040.
48. Kindler HL, Niedzwiecki D, Hollis D et al. (2007) Cancer and Leukemia Group B. 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 (Meeting Abstracts), 25, 4508.
49. Gorski DH, Beckett MA, Jaskowiak NT et al. (1999) Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res, 59, 3374-3378.
50. Geng L, Donnelly E, McMahon G et al. (2001) Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res, 61, 2413-2419.
51. Rajalingam K, Schreck R, Rapp UR, Albert S (2007) Ras oncogenes and their downstream targets. Biochim Biophys Acta, 1773, 1177-1195.
52. Shields JM, Pruitt K, McFall A, Shaub A, Der CJ (2000) Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol, 10, 147-154.
53. Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res, 49, 4682-4689.
54. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 53, 549-554.
55. Willumsen BM, Norris K, Papageorge AG, Hubbert NL, Lowy DR (1984) Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J, 3, 2581-2585.
56. James GL, Brown MS, Cobb MH, Goldstein JL (1994) Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells. J Biol Chem, 269, 27705-27714.
57. Sepp-Lorenzino L, Ma Z, Rands E et al. (1995) A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res; 55, 5302-5309.
58. End DW, Smets G, Todd AV et al. (2001) Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res, 61, 131-137.
59. Kohl NE, Omer CA, Conner MW et al. (1995) Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med, 1, 792-797.
60. Zujewski J, Horak ID, Bol CJ et al. (2000) Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol, 18, 927-941.
61. Crul M, de Klerk GJ, Swart M et al. (2002) Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol, 20, 2726-2735.
62. Johnston SR, Hickish T, Ellis P et al. (2003) Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol, 21, 2492-2499.
63. Macdonald JS, McCoy S, Whitehead RP et al. (2005) A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study. Invest New Drugs, 23, 485-487.
64. Van Cutsem E, van de Velde H, Karasek P et al. (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol, 22, 1430-1438.
65. Walker K, Olson MF (2005) Targeting Ras and Rho GTPases as opportunities for cancer therapeutics. Curr Opin Genet Dev, 15, 62-68.
66. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer, 3, 11-22.
67. Lobell RB, Omer CA, Abrams MT et al. (2001) Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res, 61, 8758-8768.
68. Martin NE, Brunner TB, Kiel KD et al. (2004) 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.
69. Britten CD, Rowinsky EK, Soignet S et al. (2001) A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies. Clin Cancer Res, 7, 3894-3903.
70. Lobell RB, Liu D, Buser CA et al. (2002) Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl: protein transferase type-I. Mol Cancer Ther, 1, 747-758.
71. Cortes J, Albitar M, Thomas D et al. (2003) Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood, 101, 1692-1697.
72. Crooke ST (1999) Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta, 1489, 31-44.
73. Tamm I, Dorken B, Hartmann G (2001) Antisense therapy in oncology: new hope for an old idea? Lancet, 358, 489-497.
74. Monia BP, Johnston JF, Ecker DJ, Zounes MA, Lima WF, Freier SM (1992) Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem, 267, 19954-19962.
75. Adjei AA, Dy GK, Erlichman C et al. (2003) A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res, 9, 115-123.
76. Alberts SR, Schroeder M, Erlichman C et al. (2004) 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.
77. McCubrey JA, Steelman LS, Chappell WH et al. (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta, 1773, 1263-1284.
78. Hoshino R, Chatani Y, Yamori T et al. (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene, 18, 813-822.
79. Allen LF, Sebolt-Leopold J, Meyer MB (2003) CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol, 30, 105-116.
80. Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer, 4, 937-947.
81. Lorusso PM, Adjei AA, Varterasian M et al. (2005) Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol, 23, 5281-5293.
82. Rinehart J, Adjei AA, Lorusso PM et al. (2004) 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.
83. Wilhelm SM, Carter C, Tang L et al. (2004) Trail PA. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res, 64, 7099-7109.
84. Siu LL, Awada A, Takimoto CH et al. (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res, 12, 144-151.
85. Wallace JA, Locker G, Nattam S et al. (2007) Sorafenib (S) plus gemcitabine (G) for advanced pancreatic cancer (PC): A phase II trial of the University of Chicago Phase II Consortium. J Clin Oncol (Meeting Abstracts), 25, 4608.
86. Downward J, Yarden Y, Mayes E et al. (1984) Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature, 307, 521-527.
87. Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR. (1991) Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol, 163, 111-116.
88. Lemoine NR, Hughes CM, Barton CM et al. (1992) The epidermal growth factor receptor in human pancreatic cancer. J Pathol, 166, 7-12.
89. Moscatello DK, Holgado-Madruga M, Godwin AK et al. (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res, 55, 5536-5539.
90. Bloomston M, Bhardwaj A, Ellison EC, Frankel WL (2006) Epidermal growth factor receptor expression in pancreatic carcinoma using tissue microarray technique. Dig Surg, 23, 74-79.
91. Funatomi H, Itakura J, Ishiwata T et al. (1997) Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. Int J Cancer, 72, 512-517.
92. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M (1993) Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res, 13, 565-569.
93. Ueda S, Ogata S, Tsuda H et al. (2004) The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas, 29, e1-8.
94. Tobita K, Kijima H, Dowaki S et al. (2003) Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int J Mol Med, 11, 305-309.
95. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell, 4, 121-133.
96. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH (1983) Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med, 1, 511-529.
97. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J (1984) Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res, 44, 1002-1007.
98. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J (1995) Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res, 1, 1311-1318.
99. Bruns CJ, Harbison MT, Davis DW et al. (2000) 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.
100. Overholser JP, Prewett MC, Hooper AT, Waksal HW, Hicklin DJ (2000) Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer, 89, 74-82.
101. Buchsbaum DJ, Bonner JA, Grizzle WE et al. (2002) Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys, 54, 1180-1193.
102. Arnoletti JP, Buchsbaum DJ, Huang ZQ et al. (2004) Mechanisms of resistance to Erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells. J Gastrointest Surg, 8, 960-969; discussion 969-970.
103. Xiong HQ, Rosenberg A, LoBuglio A et al. (2004) 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, 22, 2610-2616.
104. Philip PA, Benedetti J, Fenoglio-Preiser C et al. (2007) 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. ASCO Meeting Abstracts, 25, 4509.
105. Bangard C, Gossmann A, Papyan A, Tawadros S, Hellmich M, Bruns CJ (2005) Magnetic resonance imaging in an orthotopic rat model: blockade of epidermal growth factor receptor with EMD72000 inhibits human pancreatic carcinoma growth. Int J Cancer, 114, 131-138.
106. Graeven U, Kremer B, Sudhoff T et al. (2006) Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. Br J Cancer, 94, 1293-1299.
107. Lei S, Appert HE, Nakata B, Domenico DR, Kim K, Howard JM (1995) Overexpression of HER2/neu oncogene in pancreatic cancer correlates with shortened survival. Int J Pancreatol, 17, 15-21.
108. Yamanaka Y, Friess H, Kobrin MS et al. (1993) Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol, 24, 1127-1134.
109. Safran H, Iannitti D, Ramanathan R et al. (2004) Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest, 22, 706-712.
110. Redemann N, Holzmann B, von Ruden T, Wagner EF, Schlessinger J, Ullrich A (1992) Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol Cell Biol, 12, 491-498.
111. Moore MJ, Goldstein D, Hamm J et al. (2007) 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.
112. Grubbs SS, Grusenmeyer PA, Petrelli NJ, Gralla RJ (2006) Is it cost-effective to add erlotinib to gemcitabine in advanced pancreatic cancer? ASCO Meeting Abstracts, 24, 6048.
113. Kulke MH, Blaszkowsky LS, Ryan DP et al. (2007) Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol, 25, 4787-4792.
114. Chinnaiyan P, Huang S, Vallabhaneni G et al. (2005) Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res, 65, 3328-3335.
115. Iannitti D, Dipetrillo T, Akerman P et al. (2005) Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a phase I study. Am J Clin Oncol, 28, 570-575.
116. Czito BG, Willett CG, Bendell JC et al. (2006) Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol, 24, 656-662.
117. Fountzilas G, Murray S, Xiros N et al. (2007) Gemcitabine (G) combined with gefitinib in patients with inoperable or metastatic pancreatic cancer. A phase II trial. J Clin Oncol (Meeting Abstracts), 25, 15016.
118. Blaszkowsky LS, Ryan DP, Earle C et al. (2007) A phase II study of docetaxel in combination with ZD1839 (gefitinib) in previously treated patients with metastatic pancreatic cancer. J Clin Oncol (Meeting Abstracts), 25, 15080.
119. Ignatiadis M, Polyzos A, Stathopoulos GP et al. (2006) A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology, 71, 159-163.
120. Aly A, Shulkes A, Baldwin GS (2004) Gastrins, cholecystokinins and gastrointestinal cancer. Biochim Biophys Acta, 1704, 1-10.
121. Caplin M, Savage K, Khan K et al. (2000) Expression and processing of gastrin in pancreatic adenocarcinoma. Br J Surg, 87, 1035-1040.
122. Smith JP, Fantaskey AP, Liu G, Zagon IS (1995) Identification of gastrin as a growth peptide in human pancreatic cancer. Am J Physiol, 268, R135-R141.
123. Smith JP, Verderame MF, Zagon IS (1999) Antisense oligonucleotides to gastrin inhibit growth of human pancreatic cancer. Cancer Lett, 135, 107-112.
124. Clerc P, Leung-Theung-Long S, Wang TC et al. (2002) Expression of CCK2 receptors in the murine pancreas: proliferation, transdifferentiation of acinar cells, and neoplasia. Gastroenterology, 122, 428-437.
125. Chau I, Cunningham D, Russell C et al. (2006) 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.
126. Brett BT, Smith SC, Bouvier CV et al. (2002) Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol, 20, 4225-4231.
127. Shapiro J, Marshall J, Karasek P et al. (2005) 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. J Clin Oncol (Meeting Abstracts), 23, 4012.
128. Mollenhauer J, Roether I, Kern HF (1987) Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas, 2, 14-24.
129. Nagakawa T, Konishi I, Higashino Y et al. (1989) The spread and prognosis of carcinoma in the region of the pancreatic head. Jpn J Surg, 19, 510-518.
130. Nagakawa T, Kayahara M, Ueno K et al. (1992) A clinicopathologic study on neural invasion in cancer of the pancreatic head. Cancer, 69, 930-935.
131. Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science, 295, 2387-2392.
132. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev, 25, 9-34.
133. Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst, 89, 1260-1270.
134. Bramhall SR, Neoptolemos JP, Stamp GW, Lemoine NR (1997) Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol, 182, 347-355.
135. Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd MT (2004) Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res, 10, 2832-2845.
136. Crawford HC, Scoggins CR, Washington MK, Matrisian LM, Leach SD (2002) Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas. J Clin Invest, 109, 1437-1444.
137. Reich R, Thompson EW, Iwamoto Y et al. (1988) Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res, 48, 3307-3312.
138. Zervox EE, Franz MG, Salhab KF et al. (2000) Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer. J Gastrointest Surg, 4, 614-619.
139. Haq M, Shafii A, Zervos EE, Rosemurgy AS (2000) 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, 60, 3207-3211.
140. Moore MJ, Hamm J, Dancey J et al. (2003) 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.
141. Evans JD, Stark A, Johnson CD et al. (2001) A phase II trial of marimastat in advanced pancreatic cancer. Br J Cancer, 85, 1865-1870.
142. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA (2001) Marimastat as firstline therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol, 19, 3447-3455.
143. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA (2002) 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.
144. Gore M, A'Hern R, Stankiewicz M, Slevin M (1996) Tumour marker levels during marimastat therapy. Lancet, 348, 263-264.
145. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature, 420, 860-867.
146. Fosslien E (2001) Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. Ann Clin Lab Sci, 31, 325-348.
147. Trifan OC, Hla T (2003) Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. J Cell Mol Med, 7, 207-222.
148. Okami J, Yamamoto H, Fujiwara Y et al. (1999) Overexpression of cyclooxygenase-2 in carcinoma of the pancreas. Clin Cancer Res, 5, 2018-2024.
149. Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA (1999) Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res, 59, 4356-4362.
150. Tucker ON, Dannenberg AJ, Yang EK et al. (1999) Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res, 59, 987-990.
151. Ding XZ, Tong WG, Adrian TE (2000) Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res, 20, 2625-2631.
152. Tseng WW, Deganutti A, Chen MN, Saxton RE, Liu CD (2002) Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer. J Gastrointest Surg, 6, 838-843; discussion 844.
153. Funahashi H, Satake M, Dawson D et al. (2007) Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res, 67, 7068-7071.
154. Crane CH, Mason K, Janjan NA, Milas L (2003) Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer. Am J Clin Oncol, 26, S81-S84.
155. Milella M, Gelibter A, Di Cosimo S et al. (2004) Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer, 101, 133-138.
156. El-Rayes BF, Zalupski MM, Shields AF et al. (2005) A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest New Drugs, 23, 583-590.
157. Ferrari V, Valcamonico F, Amoroso V et al. (2006) Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol, 57, 185-190.
158. Kerr S, Campbell C, Legore K, Witters L, Harvey H, Lipton A (2005) Phase II trial of gemcitabine and irinotecan plus celecoxib in advanced adenocarcinoma of the pancreas. J Clin Oncol (Meeting Abstracts), 23, 4155.
159. Cheng JQ, Ruggeri B, Klein WM et al. (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA, 93, 3636-3641.
160. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR (1998) Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog, 21, 81-86.
161. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA (2004) The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene, 23, 8571-8580.
162. Ng SSW, Tsao MS, Chow S, Hedley DW (2000) Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res, 60, 5451-5455.
163. Perugini RA, McDade TP, Vittimberga FJ Jr., Callery MP (2000) Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J Surg Res, 90, 39-44.
164. Ng SS, Tsao MS, Nicklee T, Hedley DW (2001) Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res, 7, 3269-3275.
165. Bondar VM, Sweeney-Gotsch B, Andreeff M, Mills GB, McConkey DJ (2002) Inhibition of the phosphatidylinositol 30-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther, 1, 989-997.
166. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell, 12, 9-22.
167. Ito D, Fujimoto K, Mori T et al. (2006) 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.
168. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA (2005) The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. Biochem Biophys Res Commun, 331, 295-302.
169. Dormond O, Madsen JC, Briscoe DM (2007) The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem, 282, 23679-23686.
170. Land SC, Tee AR (2007) Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem, 282, 20534-20543.
171. Bruns CJ, Koehl GE, Guba M et al. (2004) Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res, 10, 2109-2119.
172. Tuncyurek P, Mayer JM, Klug F et al. (2007) 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.
173. Zitzmann K, De Toni EN, Brand S et al. (2007) The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology, 85, 54-60.
174. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res, 5, 119-127.
175. Arlt A, Gehrz A, Muerkoster S et al. (2003) Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene, 22, 3243-3251.
176. Muerkoster S, Arlt A, Witt M et al. (2003) Usage of the NF-kappaB inhibitor sulfasalazine as sensitizing agent in combined chemotherapy of pancreatic cancer. Int J Cancer, 104, 469-476.
177. Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res, 100, 11-17.
178. Nawrocki ST, Sweeney-Gotsch B, Takamori R, McConkey DJ (2004) The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther, 3, 59-70.
179. Shah SA, Potter MW, McDade TP et al. (2001) 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem, 82, 110-122.
180. Nawrocki ST, Bruns CJ, Harbison MT et al. (2002) Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther, 1, 1243-1253.
181. Ryan DP, Appleman LJ, Lynch T et al. (2006) Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors. Cancer, 107, 2482-2489.
182. Alberts SR, Foster NR, Morton RF et al. (2005) 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.
183. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res, 23, 363-398.
184. Hidaka H, Ishiko T, Furuhashi T et al. (2002) Curcumin inhibits interleukin 8 production and enhances interleukin 8 receptor expression on the cell surface:impact on human pancreatic carcinoma cell growth by autocrine regulation. Cancer, 95, 1206-1214.
185. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) 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, 67, 3853-3861.
186. Lev-Ari S, Vexler A, Starr A et al. (2007) Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines. Cancer Invest, 25, 411-418.
187. Dhillon N, Aggarwal BB, Newman RA et al. (2007) Curcumin and pancreatic cancer: Phase II clinical trial experience. ASCO Meeting Abstracts, 25, 4599.
188. Miyamoto Y, Maitra A, Ghosh B et al. (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell, 3, 565-576.
189. Thayer SP, di Magliano MP, Heiser PW et al. (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425, 851-856.
190. Feldmann G, Dhara S, Fendrich V et al. (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res, 67, 2187-2196.
191. Hakam A, Fang Q, Karl R, Coppola D (2003) Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci, 48, 1972-1978.
192. Beltran PJ, Mitchell P, Moody G et al. (2008) Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models. J Clin Oncol (Meeting Abstracts), 26, 4617.
193. Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 6, 506-520.
194. Hilbig A, Seufferlein T, Schmid RM et al. (2008) 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. J Clin Oncol (Meeting Abstracts), 26, 4621.
195. Argani P, Iacobuzio-Donahue C, Ryu B et al. (2001) Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res, 7, 3862-3868.
196. Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R, Brackett D (2005) Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol, 124, 838-845.
197. Qu CF, Li Y, Song YJ et al. (2004) MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by (213)Bi-C595 radioimmunoconjugate. Br J Cancer, 91, 2086-2093.
198. Yamasaki H, Ikeda S, Okajima M et al. (2004) Expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen in pancreatic tumors. Int J Oncol, 24, 107-113.
199. Hassan R, Bullock S, Premkumar A et al. (2007) Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelinexpressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res, 13, 5144-5149.
200. Armstrong DK, Laheru D, Ma WW et al. (2007) A phase 1 study of MORAb-009, a monoclonal antibody against mesothelin in pancreatic cancer, mesothelioma and ovarian adenocarcinoma. J Clin Oncol (Meeting Abstracts), 25, 14041.
201. Kindler HL, Gangadhar T, Karrison T et al. (2008) Final analysis of a randomized phase II study of bevacizumab (B) and gemcitabine (G) plus cetuximab (C) or erlotinib (E) in patients (pts) with advanced pancreatic cancer (PC). J Clin Oncol (Meeting Abstracts), 26, 4502.
202. Vervenne W, Bennouna J, Humblet Y et al. (2008) 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 (Meeting Abstracts), 26, 4507.
203. Ko AH, Dito E, Schillinger B et al. (2008) A phase II study of bevacizumab (BEV) plus erlotinib (ERL) in patients with gemcitabine (GEM)-refractory metastatic pancreatic cancer (MPC). J Clin Oncol (Meeting Abstracts), 26, 4516.
204. Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA (1999) Increased Cyclooxygenase-2 Expression in Human Pancreatic Carcinomas and Cell Lines: Growth Inhibition by Nonsteroidal Anti-Inflammatory Drugs. Cancer Res, 59, 4356-4362.
205. Okami J, Yamamoto H, Fujiwara Y et al. (1999) Overexpression of Cyclooxygenase-2 in Carcinoma of the Pancreas. Clin Cancer Res, 5, 2018-2024.
206. Tucker ON, Dannenberg AJ, Yang EK et al. (1999) Cyclooxygenase-2 Expression Is Up-Regulated in Human Pancreatic Cancer. Cancer Res, 59, 987-990.
207. Doucas H, Mann CD, Sutton CD et al. (2008) 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.
208. Dang T, Vo k, Washington K, Berlin J (2007) The role of Notch3 signaling pathway in pancreatic cancer. J Clin Oncol (Meeting Abstracts), 25, 21049.
209. Philip PA, Benedetti J, Fenoglio-Preiser C et al. (2007) 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 (Meeting Abstracts), 25, 4509.