title: Evaluating dual activity LPA receptor pan-antagonist/autotaxin inhibitors as anti-cancer agents in vivo using engineered human tumors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and The Center for Therapeutic Biomaterials, The University of Utah, Suite 205, Salt Lake City, UT 84108-1257, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.forename: Guanghui
authors.initials: G
authors.lastname: Yang
authors.forename: Honglu
authors.initials: H
authors.lastname: Zhang
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: 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
chemical_list: 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
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