KLK-targeted Therapies for Prostate Cancer.
Alternative treatments are urgently needed for prostate cancer, especially to address the aggressive metastatic castration-resistant disease. Proteolytic enzymes are involved in cancer growth and progression. The prostate produces several proteases, the most abundant ones being two members of the kallikrein-related peptidase (KLK) family, prostate-specific antigen (PSA) and KLK2. Despite the wide use of PSA as a clinical marker, the function(s) of PSA and other KLKs in prostate cancer are poorly known. Hypothetic roles of KLKs in prostate cancer include activities that may both promote and inhibit cancer growth and metastasis, including the antiangiogenic activity of PSA. Thus it may be possible to control prostate cancer growth by modulating the proteolytic activities of KLKs. PSA and KLK2 are especially attractive targets for prostate cancer treatment because of their proposed roles in tumor development and inhibition of angiogenesis in combination with their prostate selective expression. So far the number of molecules affecting selectively the activity of KLKs is limited and none of these are used to treat prostate cancer. Prodrugs that, after cleavage of the peptide part by PSA or KLK2, release active drug molecules, and PSA-targeted therapeutic vaccines have already been tested clinically in humans and the first results have been encouraging. Although KLKs are attractive targets for prostate cancer treatment, much remains to be done before their potential can be fully elucidated. The objective of this review is to address the current state of the KLKs as novel therapeutic targets for prostate cancer treatment.
Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
Koistinen
K
Hannu
Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
Mattsson
M
Johanna
Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
Stenman
S
Ulf-Håkan
KLK2; KLK3; PSA; hK2; kallikrein; peptide; prodrug; prostate cancer; serpin; therapy; vaccine
Clin Cancer Res. 2000 Jan;6(1):160-5
10656445
Nat Rev Cancer. 2010 Apr;10(4):278-92
20300104
Prostate. 2010 May 15;70(7):788-96
20058238
Biol Chem. 2010 Apr;391(4):333-43
20180648
Clin Cancer Res. 2001 Jun;7(6):1533-8
11410487
Prostate. 2007 Feb 15;67(3):312-29
17143882
Drug Discov Today. 2008 Nov;13(21-22):944-51
18725320
Nat Clin Pract Urol. 2005 Apr;2(4):174-82
16474760
Prostate. 2011 Nov;71(15):1595-607
21394741
J Urol. 2013 Apr;189(4):1421-6
23142202
Prostate. 2003 Aug 1;56(3):212-9
12772191
Cancer Res. 2007 Jun 1;67(11):5221-30
17545602
Br J Urol. 1997 Mar;79 Suppl 1:53-60
9088274
Neoplasia. 2005 Mar;7(3):241-52
15799824
Eur J Biochem. 2004 Feb;271(3):607-13
14728688
Adv Drug Deliv Rev. 2011 Jan-Feb;63(1-2):3-23
21237228
Prostate. 2001 Jun 15;48(1):1-6
11391681
Prostate. 2008 Aug 1;68(11):1143-51
18500692
Tumour Biol. 1999;20 Suppl 1:43-51
10628409
J Clin Oncol. 2002 Apr 1;20(7):1874-9
11919247
Nat Rev Drug Discov. 2007 Apr;6(4):273-86
17396134
PLoS One. 2013;8(2):e57056
23451143
J Natl Cancer Inst. 2003 Jul 2;95(13):990-1000
12837835
J Biol Chem. 2009 Nov 27;284(48):32989-94
19819870
Theranostics. 2012;2(2):156-78
22400063
EMBO J. 2012 Apr 4;31(7):1630-43
22367392
Clin Chem. 2007 Aug;53(8):1423-32
17573418
Cancer Res. 1998 Jun 15;58(12):2537-40
9635575
Endocr Rev. 2010 Aug;31(4):407-46
20103546
Nucleic Acids Res. 2009 Jan;37(Database issue):D239-43
18776217
Acta Oncol. 2011 Jun;50 Suppl 1:61-75
21604943
Prostate. 2005 Jun 1;63(4):324-9
15599939
PLoS One. 2011 Apr 27;6(4):e19302
21556330
Mol Cell Endocrinol. 2012 Sep 5;360(1-2):59-67
22465099
Nat Rev Cancer. 2008 Apr;8(4):268-78
18337732
Nat Rev Cancer. 2007 Oct;7(10):800-8
17851543
J Mol Biol. 1999 Jul 9;290(2):525-33
10390350
Cell. 2011 Mar 4;144(5):646-74
21376230
Chem Biol. 2008 Jul 21;15(7):665-74
18635003
Nat Rev Cancer. 2006 Mar;6(3):227-39
16498445
Nat Rev Drug Discov. 2006 Sep;5(9):785-99
16955069
J Biol Chem. 2006 May 5;281(18):12555-60
16527822
J Natl Cancer Inst. 1999 Oct 6;91(19):1635-40
10511590
Biochimie. 2010 Nov;92(11):1546-67
20615447
Lancet. 1994 Dec 10;344(8937):1594-8
7527116
Clin Cancer Res. 1995 Oct;1(10):1089-94
9815898
Biol Chem. 2012 Dec;393(12):1365-90
23667899
Bioorg Med Chem. 2007 Jul 15;15(14):4973-84
17502149
J Natl Cancer Inst. 2007 Mar 7;99(5):376-85
17341729
Nat Med. 2011 Mar;17(3):320-9
21383745
Nat Rev Drug Discov. 2010 Sep;9(9):690-701
20811381
Eur J Cancer. 2010 Dec;46(18):3434-44
20933385
Trends Pharmacol Sci. 2012 Dec;33(12):623-34
23089221
Biol Chem. 2010 Apr;391(4):357-74
20180638
ACS Med Chem Lett. 2013 Dec 16;5(2):162-5
24900791
Prostate. 2012 Oct 1;72(14):1588-94
22430591
Bioconjug Chem. 2006 May-Jun;17(3):787-96
16704219
Eur J Biochem. 2000 Oct;267(20):6212-20
11012675
Int J Clin Pract. 2011 Nov;65(11):1180-92
21995694
Biol Chem. 2008 Jun;389(6):633-42
18627344
Chem Biol. 2009 Jun 26;16(6):633-43
19549601
Mol Cancer Ther. 2002 May;1(7):451-9
12479263
Eur Urol. 2012 Feb;61(2):290-306
22001436
Oncoimmunology. 2013 May 1;2(5):e24523
23762812
Prostate. 2006 Mar 1;66(4):358-68
16302271
Prostate. 1988;12(1):39-46
2450341
Cancer. 2011 Mar 15;117(6):1210-9
20960520
J Pept Sci. 2007 May;13(5):348-53
17436344
J Biol Chem. 2008 Nov 7;283(45):30433-7
18650443
Anticancer Drugs. 2011 Mar;22(3):213-22
21150773
ChemMedChem. 2011 Dec 9;6(12):2170-8
21953896
Biol Chem. 2010 Apr;391(4):299-310
20180639
Nat Rev Cancer. 2004 Nov;4(11):876-90
15516960
CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
21296855
Nat Med. 2000 Nov;6(11):1248-52
11062536
J Exp Clin Cancer Res. 2010 Dec 28;29:171
21189143
Scand J Urol Nephrol Suppl. 2005 May;(216):64-81
16019759
Mol Cancer Res. 2008 Jun;6(6):1043-51
18567807
Cancer Res. 2008 Sep 1;68(17):7110-9
18757426
Bioorg Med Chem Lett. 2002 Sep 2;12(17):2459-61
12161157
Urology. 1997 Jun;49(6):857-62
9187691
Prostate. 2008 Jun 15;68(9):945-54
18386289