Evaluating dual activity LPA receptor pan-antagonist/autotaxin inhibitors as anti-cancer agents in vivo using engineered human tumors.
Using an in situ cross-linkable hydrogel that mimics the extracellular matrix (ECM), cancer cells were encapsulated and injected in vivo following a "tumor engineering" strategy for orthotopic xenografts. Specifically, we created several three-dimensional (3D) human tumor xenografts and evaluated the tumor response to BrP-LPA, a novel dual function LPA antagonist/ATX inhibitor (LPAa/ATXi). First, we describe the model system and the optimization of semi-synthetic ECM (sECM) compositions and injection parameters for engineered xenografts. Second, we summarize a study to compare angiogenesis inhibition in vivo, comparing BrP-LPA to the kinase inhibitor sunitinib maleate (Sutent). Third, we compare treatment of engineered breast tumors with LPAa/ATXi alone with treatment with Taxol. Fourth, using a re-optimized sECM for non-small cell lung cancer cells, we created reproducibly sized subcutaneous lung tumors and evaluated their response to treatment with LPAa/ATXi. Fifth, we summarize the data on the use of LPAa/ATXi to treat a model for colon cancer metastasis to the liver. Taken together, these improved, more realistic xenografts show considerable utility for evaluating the potential of novel anti-metastatic, anti-proliferative, and anti-angiogenic compounds that modify signal transduction through the LPA signaling pathway.
Xu
Xiaoyu
X
Department of Medicinal Chemistry and The Center for Therapeutic Biomaterials, The University of Utah, Suite 205, Salt Lake City, UT 84108-1257, USA.
Yang
Guanghui
G
Zhang
Honglu
H
Prestwich
Glenn D
GD
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000737:chemistry; D005260:Female; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D010168:Palmitates / Q000737:chemistry / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000099189:Lysophospholipase D
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020100:Hydrogels; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D063065:Organophosphonates; D010168:Palmitates; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D
Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1908-12
8127904
Cancer. 2007 Nov 15;110(10):2119-52
17939129
Cancer Biol Ther. 2005 Aug;4(8):846-7
16123582
Int J Cancer. 2001 Apr 15;92(2):249-56
11291053
Neuro Oncol. 2005 Apr;7(2):106-21
15831230
ChemMedChem. 2007 May;2(5):679-90
17443831
CA Cancer J Clin. 2007 May-Jun;57(3):168-85
17507442
Biomaterials. 2008 May;29(15):2336-47
18313745
Angiogenesis. 2008;11(3):301-10
18504643
J Cell Biochem. 2007 Aug 15;101(6):1370-83
17492655
Tissue Eng. 2006 Aug;12(8):2131-40
16968154
Cancer Res. 1987 Oct 1;47(19):5132-40
3621199
Exp Cell Res. 1995 Jan;216(1):51-64
7813633
J Med Chem. 2003 Mar 27;46(7):1116-9
12646019
Am J Physiol Cell Physiol. 2005 Jul;289(1):C2-11
15728708
Cancer. 1993 Jun 15;71(12 Suppl):4252-66
8508388
Biochim Biophys Acta. 2002 May 23;1582(1-3):18-25
12069806
Mol Cancer Res. 2007 Nov;5(11):1201-11
18025263
J Immunol. 1999 Feb 15;162(4):2049-56
9973477
Int J Cancer. 2006 Aug 1;119(3):712-7
16496381
Cell. 1996 Aug 9;86(3):353-64
8756718
Cancer Res. 2009 Jul 1;69(13):5441-9
19509223
Anticancer Res. 1997 Jul-Aug;17(4A):2419-25
9252657
Arterioscler Thromb Vasc Biol. 2000 Apr;20(4):1013-9
10764666
N Engl J Med. 2002 Jan 10;346(2):92-8
11784875
Cancer. 2010 Apr 1;116(7):1739-50
20143443
Biomaterials. 2005 Oct;26(30):6054-67
15958243
Semin Oncol. 2002 Apr;29(2):126-35
11951210
Curr Drug Targets. 2008 Aug;9(8):698-708
18691016
Tissue Eng. 2007 May;13(5):1091-101
17582839
J Cell Biochem. 2004 Aug 15;92(6):1115-40
15258897
J Cell Biol. 1996 Nov;135(4):1071-83
8922387
Nanomedicine. 2005 Jun;1(2):110-4
17292065
Macromol Biosci. 2009 Jan 9;9(1):20-8
18839402
Acc Chem Res. 2008 Jan;41(1):139-48
17655274
Brain Tumor Pathol. 2004;21(2):69-73
15700836
J Biol Chem. 2003 Aug 1;278(31):29000-8
12746434
Recent Pat Anticancer Drug Discov. 2006 Jan;1(1):105-19
18221030
Int J Oncol. 2008 Sep;33(3):525-32
18695882
Cell. 2006 Aug 25;126(4):677-89
16923388
Ann Oncol. 2006 Sep;17 Suppl 10:x65-70
17018754
Lab Invest. 1992 Dec;67(6):804; author reply 804-8
1460871
Nat Med. 1995 Jan;1(1):27-31
7584949
Prog Lipid Res. 2007 Mar;46(2):145-60
17459484
Cancer Res. 1983 May;43(5):2159-66
6187444
Cancer Gene Ther. 2002 Feb;9(2):197-201
11857038
Br J Exp Pathol. 1972 Apr;53(2):216-24
4555714
Clin Cancer Res. 2003 Jan;9(1):327-37
12538485
Cancer. 1984 Jan 15;53(2):360-7
6690020
Biochemistry. 1986 Jan 28;25(2):312-8
2937447
Dis Markers. 2008;24(1):41-50
18057535
Cell Signal. 2008 Oct;20(10):1804-14
18627789
Curr Oncol Rep. 2008 Jul;10(4):277-82
18778551
Vasa. 2007 Nov;36(4):253-60
18357917
Trans Ophthalmol Soc U K. 1980 Sep;100(3):346-53
6171066
Nat Rev Drug Discov. 2007 Apr;6(4):273-86
17396134
Biochim Biophys Acta. 2008 Sep;1781(9):588-94
18454946
Biochim Biophys Acta. 1990 Jun 1;1032(1):89-118
1694687
Nat Rev Cancer. 2003 Aug;3(8):582-91
12894246
Int J Cancer. 1981 Dec;28(6):777-83
6277800
J Clin Oncol. 2007 Mar 1;25(7):884-96
17327610
Cancer Chemother Pharmacol. 2008 Dec;63(1):117-26
18338172
Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6027-32
15837931
J Cell Biol. 2002 Jul 22;158(2):227-33
12119361
Cancer Res. 2006 Apr 1;66(7):3351-4, discussion 3354
16585151
Arch Surg. 1989 Sep;124(9):1021-2
2673139
Organogenesis. 2008 Jan;4(1):42-7
19279714
Circulation. 2005 Sep 13;112(11):1522-4
16157781
J Gastrointest Surg. 2008 Jun;12(6):1074-80
18057994