Small molecule tyrosine kinase inhibitors in pancreatic cancer.
Pancreatic cancer has proven to be chemo-resistant, with gemcitabine being the only cytotoxic agent approved for advanced pancreatic cancer since 1996. Tyrosine kinase inhibitors represent a newer generation of chemotherapeutic agents targeting specific tumor pathways associated with carcinogenesis including cell cycle control, signal transduction, apoptosis and angiogenesis. These agents present a more selective way of treating pancreatic cancer. Erlotinib is the prototype of the tyrosine kinase inhibitors with proven efficacy in advanced pancreatic cancer and has been recently approved in that setting. Multiple other tyrosine kinase inhibitors targeting the VEGFR, PDGFR, and Src kinases are in various phases of clinical trials testing. The preliminary results of these trials have been disappointing. Current challenges in pancreatic cancer clinical trials testing include improving patient selection, identifying effective combinations, improving the predictive value of current preclinical models and better study designs. This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development.
Gupta
Sachin
S
Department of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, MI, USA.
El-Rayes
Bassel F
BF
Ann Surg. 2002 Dec;236(6):738-49; discussion 749
12454512
Anticancer Res. 1993 May-Jun;13(3):565-9
8317885
Physiol Rev. 1999 Oct;79(4):1283-316
10508235
Semin Oncol. 2003 Feb;30(1 Suppl 1):3-11
12644979
Curr Opin Oncol. 1998 Jul;10(4):362-6
9702405
Cancer Res. 2002 Oct 1;62(19):5476-84
12359756
Cancer Metastasis Rev. 2003 Dec;22(4):337-58
12884910
J Clin Oncol. 1997 Jun;15(6):2403-13
9196156
Cancer Lett. 2006 Feb 28;233(2):328-37
15893416
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Am J Pathol. 2004 Jul;165(1):35-52
15215160
J Clin Invest. 2003 May;111(9):1287-95
12727920
Lancet. 2008 Jun 21;371(9630):2101-8
18514303
Lancet Oncol. 2008 Feb;9(2):132-8
18249033
EMBO J. 2000 Jul 3;19(13):3159-67
10880430
J Clin Oncol. 2004 Sep 15;22(18):3776-83
15365074
Clin Cancer Res. 2006 Jan 1;12(1):144-51
16397036
Annu Rev Cell Dev Biol. 1997;13:513-609
9442882
Pancreas. 2002 Aug;25(2):122-9
12142733
J Clin Oncol. 2010 Aug 1;28(22):3605-10
20606093
J Clin Oncol. 2005 Feb 10;23(5):1011-27
15585754
J Clin Oncol. 2001 Sep 15;19(18 Suppl):32S-40S
11560969
Int J Oncol. 2004 Jul;25(1):203-10
15202007
Int J Clin Oncol. 2001 Apr;6(2):59-65
11706751
J Clin Oncol. 2003 Jul 15;21(14):2787-99
12860957
Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
11252954
J Clin Oncol. 2007 May 20;25(15):1960-6
17452677
Semin Oncol. 2006 Aug;33(4):369-85
16890793
Int J Cancer. 2000 Jan 1;85(1):27-34
10585578
Br J Surg. 1995 Jan;82(1):111-5
7881926
J Pathol. 1992 Jan;166(1):7-12
1538276
Drug Resist Updat. 2006 Feb-Apr;9(1-2):1-18
16621676
Cancer Res. 2000 Apr 15;60(8):2178-89
10786682
Cancer Res. 2005 Nov 15;65(22):10371-80
16288027
Clin Cancer Res. 2003 Dec 15;9(17):6534-44
14695158
J Clin Oncol. 2005 Aug 20;23(24):5474-83
16027439
Cell. 2000 Oct 13;103(2):211-25
11057895
Clin Adv Hematol Oncol. 2003 Jul;1(7):430-4
16258429
Br J Cancer. 1999 Mar;79(9-10):1553-63
10188906
Pharmacol Ther. 1999 May-Jun;82(2-3):231-9
10454200
Cell. 2006 Jun 16;125(6):1029-31
16777592
Cytokine Growth Factor Rev. 2004 Aug;15(4):275-86
15207817
Int J Cancer. 2001 May 1;92(3):361-9
11291072
Adv Cancer Res. 2000;79:1-38
10818676
J Mol Med (Berl). 1999 Jul;77(7):527-43
10494799
Int J Cancer. 2002 Nov 10;102(2):101-8
12385004
N Engl J Med. 1971 Nov 18;285(21):1182-6
4938153
Am J Clin Oncol. 2005 Dec;28(6):570-5
16317266
J Clin Oncol. 2005 May 20;23(15):3509-16
15908661
Int J Cancer. 1995 Sep 4;62(5):529-35
7665222
J Clin Oncol. 2002 Nov 1;20(21):4368-80
12409337
Anticancer Drugs. 2007 Jun;18(5):569-79
17414626
Semin Oncol. 2006 Dec;33(6 Suppl 11):S10-3
17178279
Science. 1995 Mar 24;267(5205):1782-8
7892601
Clin Cancer Res. 2003 Apr;9(4):1546-56
12684431
Cancer Invest. 2007 Oct;25(7):647-57
18027154
Anticancer Res. 1998 Nov-Dec;18(6B):4613-9
9891528
JAMA. 2007 Jan 17;297(3):267-77
17227978
Cancer Res. 2004 Oct 1;64(19):7099-109
15466206