Steven P. Balk

Cancer Biology Program - Hematology Oncology Division
Beth Israel Deaconess Medical Center
Harvard Medical School
Harvard Institutes of Medicine, Room 1050
330 Brookline Avenue
Boston, MA 02115
Tel: (617) 667-3918
Fax: (617) 667-5339
Email: sbalk@bidmc.harvard.edu
5 postdoctoral fellows, 2 oncology clinical fellows

The laboratory conducts basic and translational research in cancer biology, with a focus on prostate cancer and the proteins/pathways that are critical for tumor development and progression. One such critical protein is androgen receptor (AR), a steroid hormone receptor that is highly expressed in luminal epithelial cells of normal prostate and in most prostate cancers. The majority of prostate cancer patients respond to androgen deprivation therapies (surgical or medical castration), but they invariably relapse with more aggressive tumors that have been termed hormone refractory, androgen independent, or castration recurrent prostate cancer. Significantly, AR is highly expressed and AR transcriptional activity is reactivated in these relapsed tumors, despite castrate levels of androgens. Identification of the critical functions of AR in prostate cancer, determining the molecular basis for AR reactivation in prostate cancers that relapse after androgen deprivation therapy, and developing novel therapies that can abrogate AR activity in primary and relapsed prostate cancers are overall major research objectives in the lab. One particular approach to the latter objective has been to identify AR antagonists than can enhance the recruitment of transcriptional corepressor proteins (NCoR and SMRT), and may therefore function as potent or selective AR antagonists in prostate.

A major recent advance in prostate cancer biology was the identification of frequent gene fusions between a highly androgen regulated gene, TMPRSS2, and genes encoding Ets family transcription factors (primarily ERG). The gene fusions appear to result in AR mediated overexpression of ERG, and may be an initiating event in prostate cancer. These observations indicate that TMPRSS2-ERG fusion genes are critical transcriptional targets of AR in prostate cancer, and that hormonal therapies should be directed at suppressing expression of these genes. Therefore, regulation of TMPRSS2-ERG gene expression and its contribution to prostate cancer in patients and mouse models is a further focus of research.

An additional mechanism that contributes to the majority of prostate cancers is loss of PTEN, with subsequent PI3 kinase pathway activation. One critical and well-studied target of PI3 kinase is Akt, but there are clearly additional proteins activated downstream of PI3 kinase that may be therapeutic targets in prostate cancer. One such protein is the nonreceptor tyrosine kinase Bmx/Etk, a member of the Tec family of tyrosine kinases that contain pleckstrin homology domains and are activated downstream of PI3 kinase. We are currently studying the mechanisms mediating Bmx activation, its downstream targets, and its contribution to prostate cancer in cell line and xenograft models, and transgenic/knockout mouse models.

References:

• Hodgson,M.C., Astapova,I., Cheng,S., Lee,L.J., Verhoeven,M.C., Choi,E., Balk,S.P., and Hollenberg,A.N. (2005). The androgen receptor recruits nuclear receptor CoRepressor (N-CoR) in the presence of mifepristone via its N and C termini revealing a novel molecular mechanism for androgen receptor antagonists. J. Biol. Chem. 280, 6511-6519.
• Chen,S., Xu,Y., Yuan,X., Bubley,G.J., and Balk,S.P. (2006). Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc. Natl. Acad. Sci. U. S. A 103, 15969-15974.
• Stanbrough,M., Bubley,G.J., Ross,K., Golub,T.R., Rubin,M.A., Penning,T.M., Febbo,P.G., and Balk,S.P. (2006). Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66, 2815-2825.
• Jiang,X., Borgesi,R.A., McKnight,N.C., Kaur,R., Carpenter,C.L., and Balk,S.P. (2007). Activation of nonreceptor tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and ErbB3 in prostate cancer cells. J. Biol. Chem. 282, 32689-32698.