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Clinical-translational approaches to the Nm23-H1 metastasis suppressor
Patricia S Steeg1, Christine E Horak, Kathy D Miller
1Women'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
Abstract:
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.
Insights
Nm23-H1, a metastasis suppressor gene, inhibits cancer spread without affecting primary tumor size. High-dose medroxyprogesterone acetate (MPA) may re-induce Nm23-H1 to limit metastatic colonization in breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Nm23-H1 is the first identified metastasis suppressor gene.
- Nm23-H1 inhibits cancer metastasis, not primary tumor growth.
- Its mechanisms involve kinase activity, binding proteins, and gene expression regulation.
Purpose of the Study:
- To investigate the role of Nm23-H1 in metastasis suppression.
- To explore the potential of medroxyprogesterone acetate (MPA) in re-expressing Nm23-H1.
- To evaluate MPA's efficacy in limiting metastatic colonization in breast cancer.
Main Methods:
- Studied Nm23-H1's histidine kinase activity towards substrates like ATP-citrate lyase.
- Investigated Nm23-H1's interaction with binding proteins.
- Analyzed Nm23-H1's downstream gene expression, focusing on EDG2.
- Initiated a Phase II clinical trial for high-dose MPA in breast cancer patients.
Main Results:
- Nm23-H1 suppresses metastasis through multiple molecular mechanisms.
- Nm23-H1 expression is inversely associated with EDG2.
- A Phase II trial is evaluating MPA's effect on Nm23-H1 re-expression and metastatic colonization.
Conclusions:
- Nm23-H1 is a critical suppressor of metastatic colonization.
- Targeting Nm23-H1 re-expression may offer a novel therapeutic strategy for breast cancer.
- MPA shows potential in reactivating Nm23-H1 to combat cancer metastasis.
