The PI discovered the first metastasis suppressor gene, Nm23 (NME). Basic and translational research has investigated the role of NME1 in the regulation of tumor metastasis. Eleven transfection studies have documented that overexpression of NME1 or NME2 in various tumor cell lines resulted in a 50-90% decrease in tumor metastatic potential in vivo. The mechanism of Nm23 suppression of metastasis is incompletely understood and likely complex. In the past year we have returned to the histidine protein kinase activity of NME1. NME1 has been reported to be a histidine protein kinase but the contribution of this function has been impossible to determine, as histidine is destroyed under acidic and heat conditions used for simple SDS-PAGE. Based on a recent publication of an anti- phospho-histidine monoclonal antibody, we have been able to quantify and visualize NME-pHis for the first time. Using sets of triple-negative breast cancer cell lines expressing a vector or NME1, total NME1 and pHis-NME1 levels were often directly correlated. NME1 mutants were overexpressed in breast cancer cells that separated the NDP kinase and histidine protein kinase activities of NME1. In these mutants, the histidine protein kinase expression of NME1 best correlated with inhibition of breast cancer motility in vitro. The data suggest that the histidine protein kinase activity of NME may be important for its metastasis suppression. A second project completed concerned the inverse relationship of NME1 and the lysophosphatidic acid receptor 1 (LPA1). In previous years, I found that NME expression was inverse to LPA1 in breast cancer cell line and patient tumors. Transfection experiments established that some of NME metastatsis suppressor function was due to the LPA1 pathway. I then hypothesized that an LPA1 inhibitor could prevent breast cancer metastasis and obtained preliminary in vivo data using Debio 0719. We have now investigated two orally available LPA1 inhibitors that could be clinical candidates, from Sanofi Aventis and Epigen Biosciences. Both are being developed for fibrosis indications. We examined multiple model systems of triple-negative breast cancer and ovarian cancer for the extent of fibrosis and the efficacy of these inhibitors. Fibrosis was low in most metastatic specimens, and both inhibitors were without activity in vivo. The data suggest that fibrosis is not a clinical target in untreated breast cancer metastasis and that orally available LPA1 inhibitors need further optimization.
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