The autotaxin (ATX)->lysophosphatidic acid (LPA)->LPA-receptor (LPAR) signaling axis stimulates the proliferation, motility, invasion, and metastasis of tumor cells;its components are upregulated in several carcinomas. During the prior funding period, we made major discoveries about ATX ->LPA ->LPAR axis as important oncogenic mechanisms, which now provide the fundamental principles from which to propose developing drug-like compounds that prevent cancer invasion and metastasis by disrupting this signaling axis. ATX, a lysophospholipase D that generates LPA, is among the 40 most upregulated genes in metastatic cancers. Overexpression of ATX or LPAR leads to malignant transformation, metastasis, and resistance to cell death. Our laboratory evidence to date shows that: 1) Selective inhibitors of ATX inhibit metastasis. 2) LPA1- receptor knockout (KO) mice are completely resistant to metastasis of B16 syngeneic melanoma. 3) An LPA1/3 antagonist markedly reduces melanoma metastasis. 4) LPA bromophosphonate, a dual-action inhibitor of ATX and also antagonist of LPA1/2/3/4 receptors, not only inhibits metastasis but also inhibits tumor growth in vivo. Based on these findings, we propose to test three translational hypotheses: 1) Long-lasting inhibition of ATX-mediated LPA production by cancer cells will inhibit tumor metastasis. 2) Inhibition of LPA1 in the host will block metastasis. 3) Multi-targeting of ATX and LPA1 will reduce tumor growth and provide superior chemoprevention against metastasis over monotherapy. First, we will improve small-molecule ATX inhibitors to achieve long-lasting reduction of LPA production in the tumor microenvironment. To this end, we will increase the structural diversity of available ATX inhibitors and improve the LPA1 receptor specificity of our dual-action ATX inhibitor/LPAR antagonist leads by using high throughput screening, in silico drug design utilizing the new ATX crystal structure, and medicinal chemistry. We will mechanistically characterize the most potent leads in enzymatic and cancer invasion assays in vitro and determine their toxicokinetic profiles in vivo. We will compare the in vivo efficacy of new ATX-specific inhibitors alone, in combination with the LPA1- specific antagonist AM095, and the dual-action ATX/LPA1 inhibitors in different murine metastasis models. We envision that the drug candidates we will identify will ultimately be used as part of the multimodal treatment of cancers for the prevention of metastasis prior to/after removal of the primary tumor as is often the case for melanomas.

Public Health Relevance

The autotaxin (ATX)->lysophosphatidic acid (LPA)->LPA-receptor (LPAR) signaling axis stimulates the proliferation, motility, invasion, and metastasis of tumor cells;its components are upregulated in several carcinomas. The long-term objective of our research is to lay the foundation for drugs targeting the ATX-LPA-LPAR axis in cancer therapy and identify drug-like lead compounds suitable to begin translational research for use in oncology patients. We envision that the drug candidates we will identify will ultimately be used as part of the multimodal treatment of cancers for the prevention of metastasis prior to/after removal of the primary tumor as is often the case for melanomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092160-13
Application #
8626164
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2001-08-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$289,149
Indirect Cost
$93,616
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Lee, Sue-Chin; Fujiwara, Yuko; Liu, Jianxiong et al. (2015) Autotaxin and LPA1 and LPA5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis. Mol Cancer Res 13:174-85
Panupinthu, N; Yu, S; Zhang, D et al. (2014) Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene 33:2846-56
Ruisanchez, Eva; Dancs, Peter; Kerek, Margit et al. (2014) Lysophosphatidic acid induces vasodilation mediated by LPA1 receptors, phospholipase C, and endothelial nitric oxide synthase. FASEB J 28:880-90
Tigyi, Gabor (2013) New trends in lysophospholipid research. Biochim Biophys Acta 1831:1
Parrill, Abby L; Tigyi, Gabor (2013) Integrating the puzzle pieces: the current atomistic picture of phospholipid-G protein coupled receptor interactions. Biochim Biophys Acta 1831:2-12
Brindley, David N; Lin, Fang-Tsyr; Tigyi, Gabor J (2013) Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy. Biochim Biophys Acta 1831:74-85
Park, S Y; Jeong, K J; Panupinthu, N et al. (2011) Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene 30:1351-9
Panupinthu, N; Lee, H Y; Mills, G B (2010) Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression. Br J Cancer 102:941-6
Valentine, William J; Kiss, Gyongyi N; Liu, Jianxiong et al. (2010) (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. Cell Signal 22:1543-53
Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong et al. (2010) 2D binary QSAR modeling of LPA3 receptor antagonism. J Mol Graph Model 28:828-33

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