title: Targeting metastatic upper gastrointestinal adenocarcinomas.
abstract: Upper gastrointestinal (GI) tumors, including adenocarcinoma of the esophagus, stomach, pancreas, and biliary tree, have traditionally been difficult to treat with cytotoxic chemotherapeutic agents. There has been little drug development success in treating these cancers over the last 20 years, perhaps a reflection of a combination of the aggressive biology of these tumors, the void in effective and specific drug development for these varied tumors, and the lack of properly designed, biologically-based clinical trials. Recently, so called "targeted agents" have risen to the forefront in the care of cancer patients and have made strong impacts in many areas of oncology, particularly gastrointestinal stromal tumors (GIST), colon, breast, and lung cancers. Unfortunately, slow progress has been made using such agents in upper GI tumors. However, more recently, trials in some tumor types have demonstrated gains in progression free survival and overall survival. In this review, we discuss the drugs and pathways that have been most successful in the treatment of upper GI tumors and present the relevant data supporting their use for each tumor site. Additionally, we will explore a few novel pathways that may prove effective in the treatment of upper GI malignancies in the near future.
authors: Jennifer L Spratlin, Quincy Chu, Sheryl Koski, Karen King, Karen Mulder, Cross Cancer Institute, University of Alberta, T6G 1Z2, Edmonton, Alberta, Canada.
authors: Jennifer L
authors: JL
authors: Spratlin
authors: Quincy
authors: Q
authors: Chu
authors: Sheryl
authors: S
authors: Koski
authors: Karen
authors: K
authors: King
authors: Karen
authors: K
authors: Mulder
references: Nature. 2003 Oct 23;425(6960):851-6
references: 14520413
references: Gut. 2007 May;56(5):601-5
references: 16973716
references: Hepatology. 1996 Mar;23(3):455-64
references: 8617424
references: J Clin Oncol. 2010 Feb 10;28(5):780-7
references: 20048182
references: Science. 1987 Apr 3;236(4797):70-3
references: 3563490
references: N Engl J Med. 2008 Jul 24;359(4):378-90
references: 18650514
references: Oncogene. 2004 Apr 19;23(18):3151-71
references: 15094765
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1103-8
references: 15279798
references: Br J Cancer. 2008 Sep 16;99(6):868-74
references: 19238629
references: Annu Rev Cell Dev Biol. 2001;17:463-516
references: 11687497
references: FASEB J. 1999 Jan;13(1):9-22
references: 9872925
references: Mol Cancer. 2004 Oct 13;3:29
references: 15482598
references: Oncogene. 2004 May 6;23(21):3872-82
references: 15021907
references: Clin Cancer Res. 2006 Jan 1;12(1):144-51
references: 16397036
references: Science. 1997 Aug 22;277(5329):1109-13
references: 9262482
references: Ann Oncol. 1997 Feb;8(2):163-8
references: 9093725
references: Cell. 1996 Jun 14;85(6):841-51
references: 8681379
references: Nat Rev Cancer. 2002 May;2(5):361-72
references: 12044012
references: Lancet Oncol. 2009 Jan;10(1):25-34
references: 19095497
references: Cell Cycle. 2006 Jul;5(13):1426-30
references: 16855389
references: N Engl J Med. 2004 Jun 3;350(23):2335-42
references: 15175435
references: Trends Mol Med. 2008 Apr;14(4):169-78
references: 18353725
references: J Clin Oncol. 2010 Aug 1;28(22):3605-10
references: 20606093
references: Lancet Oncol. 2009 Aug;10(8):794-800
references: 19586800
references: Int J Cancer. 2006 Jan 1;118(1):139-48
references: 16003737
references: Cancer. 1993 Jul 1;72(1):37-41
references: 8508427
references: J Clin Oncol. 2006 Jul 1;24(19):3069-74
references: 16809731
references: Nature. 2003 Oct 23;425(6960):846-51
references: 14520411
references: J Cancer Res Clin Oncol. 2007 Apr;133(4):271-8
references: 17294242
references: J Clin Oncol. 2006 Oct 20;24(30):4922-7
references: 17050876
references: Ann Surg Oncol. 2007 Jun;14(6):1835-45
references: 17406950
references: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references: 16680569
references: J Clin Oncol. 2002 Aug 1;20(15):3270-5
references: 12149301
references: Invest New Drugs. 2011 Dec;29(6):1449-58
references: 20461441
references: Cell. 2010 Apr 2;141(1):52-67
references: 20371345
references: Cancer Chemother Pharmacol. 2009 Sep;64(4):777-83
references: 19169683
references: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references: 19474385
references: J Clin Oncol. 2003 Jul 15;21(14):2787-99
references: 12860957
references: Nature. 2003 Mar 20;422(6929):313-7
references: 12629553
references: J Clin Oncol. 2006 Jun 20;24(18):2903-9
references: 16782930
references: J Clin Oncol. 2007 May 20;25(15):1960-6
references: 17452677
references: BMC Cancer. 2004 Aug 04;4:43
references: 15294024
references: J Clin Oncol. 2010 Jul 20;28(21):3491-7
references: 20530271
references: J Clin Oncol. 2004 Jul 1;22(13):2610-6
references: 15226328
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: J Biol Chem. 2010 May 7;285(19):14071-7
references: 20231296
references: J Biol Chem. 2001 Feb 2;276(5):3222-30
references: 11058584
references: J Clin Oncol. 2005 Sep 20;23(27):6657-63
references: 16170173
references: N Engl J Med. 2008 Mar 13;358(11):1160-74
references: 18337605
references: Am J Med Genet A. 2010 Aug;152A(8):1875-914
references: 20635334
references: Nature. 1998 Jan 1;391(6662):90-2
references: 9422511
references: Clin Cancer Res. 2009 Sep 15;15(18):5895-901
references: 19737952
references: Nature. 1999 Feb 18;397(6720):617-21
references: 10050855
references: Cancer. 2008 Jun 15;112(12):2733-9
references: 18412149
references: Curr Opin Cell Biol. 2006 Apr;18(2):145-51
references: 16516457
references: Curr Opin Cell Biol. 2005 Dec;17(6):596-603
references: 16226444
references: Cell. 2006 Oct 6;127(1):45-8
references: 17018275
references: Cancer Cell. 2002 Mar;1(2):193-202
references: 12086877
references: Cytokine Growth Factor Rev. 1996 Oct;7(3):259-70
references: 8971481
references: Clin Cancer Res. 2010 Jan 15;16(2):390-7
references: 20068087
references: Nat Rev Cancer. 2003 Dec;3(12):903-11
references: 14737121
references: Cancer Biol Ther. 2006 Feb;5(2):238-9
references: 16552173
references: Nature. 2005 Apr 14;434(7035):913-7
references: 15829966
references: Cell Death Differ. 2007 Feb;14(2):218-29
references: 16676006
references: J Clin Oncol. 2008 Jun 20;26(18):2992-8
references: 18565886
references: Oncogene. 2003 May 15;22(19):2967-71
references: 12771948
references: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references: 17318226
references: Cancer Res. 1993 Dec 1;53(23):5822-7
references: 7694795
references: Ann Oncol. 2007 Mar;18(3):510-7
references: 17164226
references: Nat Genet. 1998 Sep;20(1):58-61
references: 9731532
references: Cell. 2000 Oct 13;103(2):253-62
references: 11057898
references: Br J Cancer. 2002 Jul 15;87(2):161-7
references: 12107836
references: Curr Opin Genet Dev. 1995 Aug;5(4):492-8
references: 7580142
references: Oncology. 2007;72(1-2):105-10
references: 18025804
references: J Biol Chem. 2004 Dec 31;279(53):55117-26
references: 15498778
references: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9346-51
references: 8790332
references: Anticancer Res. 1999 May-Jun;19(3B):2257-60
references: 10472340
references: Curr Biol. 1998 Sep 24;8(19):1083-6
references: 9768363
references: Science. 1989 Dec 8;246(4935):1306-9
references: 2479986
references: Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232
references: 7612182
references: Expert Opin Pharmacother. 2005 Feb;6(2):211-23
references: 15757418
references: Nature. 2005 Dec 15;438(7070):932-6
references: 16355210
references: Nat Rev Immunol. 2004 Aug;4(8):617-29
references: 15286728
references: J Clin Oncol. 2009 Nov 20;27(33):5513-8
references: 19858379
references: Cancer. 2007 Sep 1;110(5):1059-67
references: 17623837
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: N Engl J Med. 2008 Jan 3;358(1):36-46
references: 18172173
references: Lab Invest. 2002 Mar;82(3):285-91
references: 11896207
references: Eur J Surg Oncol. 2003 Dec;29(10):879-83
references: 14624781
references: J Clin Oncol. 2009 Jan 10;27(2):193-8
references: 19047305
references: Hepatology. 2010 Jan;51(1):255-66
references: 20034026
references: J Clin Oncol. 2010 Jun 20;28(18):2947-51
references: 20458043
references: World J Gastroenterol. 2004 Mar 1;10(5):643-8
references: 14991930
references: Nat Rev Cancer. 2004 May;4(5):335-48
references: 15122205
references: Clin Adv Hematol Oncol. 2004 Jan;2(1):17, 20, 63
references: 16163153
references: Br J Cancer. 2010 Mar 16;102(6):981-6
references: 20160718
references: J Clin Oncol. 2006 Sep 10;24(26):4293-300
references: 16908937
references: Br J Cancer. 1995 Mar;71(3):587-91
references: 7533517
references: J Clin Oncol. 2009 Jun 20;27(18):3027-35
references: 19470923
references: J Clin Oncol. 2009 Feb 20;27(6):843-50
references: 19139433
references: Carcinogenesis. 2005 Oct;26(10):1698-705
references: 15905200
references: J Pathol. 2006 Jan;208(1):17-25
references: 16294371
references: J Biol Chem. 2002 Jun 21;277(25):23028-36
references: 11948190
references: Methods Enzymol. 2006;409:493-510
references: 16793420
references: J Clin Oncol. 2005 May 20;23(15):3509-16
references: 15908661
references: Nat Rev Cancer. 2002 Mar;2(3):161-74
references: 11990853
references: Cancer. 2007 Aug 1;110(3):581-9
references: 17583545
references: J Clin Oncol. 2005 Nov 1;23(31):8033-40
references: 16258101
references: J Clin Oncol. 2003 Sep 1;21(17):3296-302
references: 12947065
references: Cancer Res. 2003 Dec 1;63(23):8451-60
references: 14679009
references: J Clin Oncol. 1997 Jun;15(6):2403-13
references: 9196156
references: Int J Cancer. 1994 Nov 15;59(4):520-9
references: 7525492
references: Ann Oncol. 2005 Apr;16(4):538-48
references: 15746148
references: Ann Oncol. 2010 Nov;21(11):2213-2219
references: 20497967
references: Am J Clin Pathol. 2001 Dec;116(6):838-45
references: 11764072
references: Lancet. 2004 Mar 27;363(9414):1049-57
references: 15051286
references: EMBO Mol Med. 2009 Sep;1(6-7):315-22
references: 20049735
references: J Surg Oncol. 1992 Nov;51(3):147-52
references: 1434639
references: BMC Genomics. 2005 Oct 04;6:139
references: 16202152
references: Genes Dev. 2001 Dec 1;15(23):3059-87
references: 11731473
references: J Clin Oncol. 2006 Nov 20;24(33):5201-6
references: 17114652
references: Cancer Res. 2010 Jul 1;70(13):5457-64
references: 20530668
references: Br J Cancer. 2010 Jan 5;102(1):68-72
references: 19935794
references: Clin Cancer Res. 2006 Sep 15;12(18):5268-72
references: 17000658
references: Science. 1992 Feb 21;255(5047):989-91
references: 1312256
references: Lancet Oncol. 2010 Jan;11(1):48-54
references: 19932054
references: J Clin Oncol. 2006 Nov 1;24(31):4991-7
references: 17075117
references: Nature. 2000 Sep 14;407(6801):249-57
references: 11001068
references: Cancer Res. 2003 Jun 15;63(12):3121-6
references: 12810638
references: Trends Biochem Sci. 1994 Apr;19(4):172-6
references: 8016868
references: Mech Dev. 2000 Mar 15;92(1):55-81
references: 10704888
references: N Engl J Med. 2010 Apr 8;362(14):1273-81
references: 20375404
references: EMBO J. 1998 Jul 1;17(13):3505-11
references: 9649421
references: Cell. 2006 Feb 10;124(3):471-84
references: 16469695
references: Aliment Pharmacol Ther. 2006 Jun 1;23(11):1535-47
references: 16696801