Identification of appropriate in vivo models to demonstrate the phenotypic consequence of modulating the autotaxin/lysophosphatidic acid receptor (ATX/LPAR) pathway

Autotaxin (ATX) is an extracellular lyso-phospholipase that cleaves choline from lysophosphatidylcholine to produce lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that stimulates the proliferation, migration and survival of many cell types and has been implicated in vascular development, inflammation and tumour progression. ATX and/or LPA receptors are over-expressed in many cancers including breast, pancreatic, glioblastoma, bladder, ovarian, prostate and renal cell carcinoma. We have developed orally bioavailable lead ATX inhibitors which show good PD/biomarker modulation in vitro and in vivo. Defining the appropriate in vivo models to demonstrate the phenotypic consequence of modulating the ATX/LPA pathway has been challenging. We have evaluated our inhibitors using orthotopic mouse models of breast and ovarian cancer and in also in the 4T1 syngeneic mouse model of metastasis. Our studies using orthotopic mouse models of breast and ovarian cancer have demonstrated maximal inhibition of circulating LPA levels with our inhibitors. This, however, has not translated into a significant reduction in primary tumour growth. In contrast, inhibition of ATX in the 4T1 syngeneic mouse model strongly inhibited spontaneous metastatic dissemination of 4T1 breast cancer cells to bone and lungs. Modulation of the ATX/LPAR pathway has been shown to inhibit the process of metastasis in the 4T1 syngeneic mouse model of metastasis. Current efforts are focused on strengthening the disease positioning and evaluating our inhibitors in cancers which exhibit a high degree of loco-regional invasion such as invasive bladder cancer and glioblastoma.

Poster presented by Pritom Shah at the NCRI Cancer Coference 2015 (Liverpool, UK)

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