Clinical-translational approaches to the Nm23-H1 metastasis suppressor.
Nm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.
Steeg
Patricia S
PS
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, MD 20892, USA. steegp@mail.nih.gov
Horak
Christine E
CE
Miller
Kathy D
KD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases / Q000187:drug effects / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000970:Antineoplastic Agents; D054778:NM23 Nucleoside Diphosphate Kinases