Patricia S. Steeg, Ph.D.
Dr. Steeg discovered the first metastasis suppressor gene, Nm23. Nm23 and other metastasis suppressors prevent the formation of metastases, with no effect on primary tumor size. Her recent studies focus on breast cancer metastatic dormancy, showing that an antagonist to the Lysophosphatidic acid receptor 1 (LPA1) emulates a metastasis suppressor gene by reducing experimental liver and lung metastases and inducing dormancy in models of triple-negative breast cancer. Dr. Steeg also investigates brain metastases of breast cancer. Her studies identify molecular events controlling brain colonization, investigate the pharmacology of the blood-tumor barrier, and determine the radiation sensitivity of brain lesions.
Molecular Characterization of Breast Cancer Progression
The Women's Cancers Section performs basic and translational research on the molecular biology of breast cancer. The vast majority of breast cancer patients succumb to metastatic disease, or complications of its treatment. The Section focuses on two aspects of breast cancer metastasis:(1) What is the role of the nm23 metastasis suppressor gene (NME) in breast cancer progression? (2) What molecular events are involved in breast cancer metastasis to the brain? The nm23 family of genes was discovered by Dr. Steeg on the basis of its reduced expression in highly metastatic murine melanoma cell lines, as compared to related, poorly metastatic cell lines. Multiple transfection studies have documented that overexpression of Nm23 in metastastic cell lines resulted in a significant decrease in metastatic potential in vivo, without an effect on tumorigenicity, establishing Nm23 as a metastasis suppressor gene. Our research on the Nm23 family of genes spans its basic biochemical mechanisms to translational development. Nm23 likely suppresses metastasis by complex mechanisms involving its histidine kinase activity and protein:protein associations. We have found that the Lysophosphatidic acid receptor 1 (LPAR1 or LPA1) is inversely expressed with regard to Nm23 in breast cancer. Overexpression of LPA1 overcame Nm23 suppression of tumor metastasis.
Recently, we have reported that a preclinical LPA1 inhibitor, Debio 0719, had no effect on primary tumor formation in two model systems but significantly suppressed metastasis development, inducing metastatic dormancy. Our lab is working to bring this new lead to the clinic. Brain metastases historically occurred in at least 15% of metastatic breast cancer patients and conferred a dismal prognosis. Brain metastases are now being diagnosed in at least one-third of metastatic patients with triple-negative or HER2-positive tumors, and are increasingly a cause of death. Both the lesions and their treatments can cause neurocognitive damage.
My group has (a) developed experimental models for brain metastasis of breast cancer; (b)profiled resected brain metastases for gene expression patterns to discover functional pathways. Genes demonstrated to influence brain metastatic capacity include HER2, PEDF, RAD51 and BARD1; (c) collaboratively determined the influence of the blood-tumor barrier on drug penetration into experimental brain metastases; (d) tested multiple compounds for the prevention or treatment of brain metastases preclinically. A few compounds have been demonstrated to partially prevent brain metastasis formation including lapatinib, vorinostat and pazopanib; none were effective in a treatment (shrinkage of established lesions) setting. New clinical trial designs will be needed to advance brain metastasis prevention.
Selected Recent Publications
- J. Natl. Cancer Inst. 106(7): dju145, 2014. [ Journal Article ]
Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner.Clin. Cancer Res. 20: 2727-39, 2014. [ Journal Article ]
Effect of inhibition of the lysophosphatidic acid receptor 1 on metastasis and metastatic dormancy in breast cancer.J. Natl. Cancer Inst. 104: 1306-1319, 2012. [ Journal Article ]
- Nature. 485: S58-S59, 2012. [ Journal Article ]
- Nat. Rev. Cancer. 11: 352-363, 2011. [ Journal Article ]
Dr. Patricia S. Steeg received her Ph.D. from the University of Maryland in 1982 and was a Jane Coffin Child Memorial Fund for Medical Research Fellow in the Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, and the Laboratory of Pathology, NCI, where she was tenured in 1992. She became Chief of the Women's Cancers Section in 1993, which was subsequently moved to the Laboratory of Molecular Pharmacology.
|Hardik Amin Ph.D.||Postdoctoral Fellow (Visiting)|
|Brunilde M. Gril, Ph.D., M.P.S.||Staff Scientist|
|Imran Khan Ph.D.||Postdoctoral Fellow (CRTA)|
|Anurag Paranjape Ph.D.||Postdoctoral Fellow (Visiting)|
|Debbie Wei B.S.||Biologist|
|Alex Man Lai Wu Ph.D.||Postdoctoral Fellow (Visiting)|