I. Nm23. The PI discovered the first metastasis suppressor gene, Nm23. Basic and translational research has investigated the role of Nm23 in the regulation of tumor metastasis. Eleven transfection studies have documented that overexpression of Nm23 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. II. LPAR1 studies. One of the potential avenues to drug a suppressor gene is to identify inverse correlates of its expression. The lysophosphatidic acid receptor (LPA1, LPAR1), a G-protein coupled receptor for the serum lysophosphatidic acid (LPA) was found to be inversely related to Nm23 expression in cell lines, human breast tumors, and knock-out animal tissues. Forced re-expression of LPA1 overcame Nm23 suppression of tumor cell motility in vitro and metastasis in vivo. We hypothesized that an inhibitor of LPA1 would act as a metastasis suppressor and have preclinically validated Debio 0719. Administration of 0719 to animals injected with breast cancer cell lines had no effect on primary tumor growth but significantly suppressed metastasis and appeared to induce metastatic dormancy. In order to identify and test orally available LPA1 inhibitors, M-CRADAs were completed with Sanofi and Epigen Biosciences to use their orally available compounds, SAR100842 and EPGN696, respectively. Results are being prepared for publication, but lack promise. III. Fibrosis. Given the clinical interest in LPA1 inhibitors for fibrosis, we determined the relationship between fibrosis and breast cancer metastasis. In ten animal models of breast cancer metastasis, fibrosis was heterogeneous and overall low. We tested two recently FDA approved compounds for idiopathic pulmonary fibrosis, nintenadine and perfiridone, both of which were inactive. IV. The mechanism of Nm23 suppression of metastasis is likely multi-factorial. Nm23 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 a phospho-histidine antibody, we have confirmed that Nm23 autophosphorylates on his 118, and are investigating the role of phospho-histidine in in vitro phenotypes including endocytosis, motility and proliferation. Data being prepared for publication indicates that Nm23 phospho-histidine is necessary but not sufficient for metastasis suppression.
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