SPOREs
Prostate
Projects
Projects
Project 5: The Androgen Receptor in Hormone Refractory Disease
Co-Principal Investigators:
Myles A. Brown, MD
Steven P. Balk, MD, PhD
Participating Institution(s):
Dana-Farber Cancer Institute
Beth Israel Deaconess Medical Center
Project 5: Specific Aims
The Specific Aims of this project are:
1) To complete the current trial of ketoconozole, hydrocortisone, and dutasteride, and initiate new phase II clinical trials of compounds that suppress AR expression or function in androgen independent CaP
2) To combine gene expression data from androgen independent CaP cell lines and xenografts with AR ChIP-on-chip from these cell lines to identify critical AR cooperating factors and regulated genes that may be therapeutic targets in androgen independent CaP
3) To validate AR regulated genes as therapeutic targets in clinical AICaP
Project 5: Studies and Results
Aim 1: Complete the current trial of ketoconozole, hydrocortisone, and dutasteride, and initiate new phase II clinical trials of compounds that suppress AR expression or function in androgen independent CaP
We have completed accrual on the ketoconozole, hydrocortisone, and dutasteride (KHAD) trial. Fifty-seven patients were accrued and 13 remain on study as of the last analysis. The response rate (PSA decline >50%) was 55%, with 24/57 patients having a >80% PSA decline. The median time to progression is 13.7 months (95% CI 4.1 to 15.7 months), which is significantly longer than published progression rates for ketoconazole that range from 5-7 months. Correlative analyses of serum hormone levels are currently underway. This trial serves as the foundation for planned studies in men with metastatic AIPCa to evaluate tissue-based endpoints of response and resistance mechanisms. The results of this study will be presented at the next ASCO meeting, and a manuscript is being prepared. We have also completed a study of mifepristone in AIPCa, based on its potential as a novel AR antagonist (Taplin et al., in press).
Aim 2: Combine gene expression data from androgen independent CaP cell lines and xenografts with AR ChIP-on-chip from these cell lines to identify critical AR cooperating factors and regulated genes that may be therapeutic targets in androgen independent CaP
We have utilized chromatin immunoprecipitation (ChIP) combined with whole genome tiled microarrays (ChIP-chip) to map AR binding sites in prostate cancer cells. To understand AR function in CRPC, we have used this method in conjunction with expression microarrays to examine AR activity in LNCaP cells versus a subline adapted to grow in androgen depleted medium (LNCaP-abl cells, which still express high levels of AR and are dependent on AR protein expression for growth). Gene expression profiling in the two cell types under optimal growth conditions showed that genes involved in cell cycle regulation and mitosis were significantly increased in LNCaP-abl as compared with LNCaP, and these same genes were increased in expression in previously reported clinical CRPC data sets (not shown). Moreover, while ChIP-chip showed that global AR binding was less extensive in the androgen depleted LNCaP-abl cells, there were significantly higher levels of AR bound to putative regulatory regions of M-phase cell cycle genes, including UBE2C/UbcH10 (an essential gene that inactivates the M-phase checkpoint). Confirmatory experiments demonstrated increased expression in LNCaP-abl relative to LNCaP cells, which was selectively repressed by AR siRNA in the LNCaP-abl cells. Consistent with UBE2C being a critical AR target gene in these cells, UBE2C shRNA selectively decreased proliferation of LNCaP-abl cells. The increased binding of AR to two putative AREs in the UBE2C enhancer was accompanied by greater recruitment of transcription factors FoxA1 and GATA2 (which we have shown to associate with bound AR) and the coactivator MED1. Taken together, these results indicate that the program of gene regulation mediated by AR after ADT may eventually switch to a set of M-phase cell cycle genes (most notably UBE2C).
Aim 3: Validate AR regulated genes as therapeutic targets in clinical AICaP
Preliminary immunohistochemical studies have shown that UBE2C is more highly expressed in advanced prostate cancer, and further studies of this and other candidate genes are in progress.
Project 5: Significance
Our results in Aim 1 strongly support a major hypothesis that residual androgens are stimulating prostate cancer growth in patients with AIPCa. The studies in Aim 2 and 3 indicate that more aggressive androgen deprivation may be effective for some period of time, but that a biologically distinct form of prostate cancer may emerge that will require additional therapies directly targeting AR.
Project 5: Plans
Follow-up clinical trials are currently being designed, including a neoadjuvant trial of abiraterone acetate versus lueprolide acetate. The studies to identify additional targets downstream of AR will also continue.
Project 5: Publications
Hodgson,M.C., Astapova,I., Hollenberg,A.N., and Balk,S.P. (2007). Activity of Androgen Receptor Antagonist Bicalutamide in Prostate Cancer Cells Is Independent of NCoR and SMRT Corepressors. Cancer Res. 67, 8388-8395.
Wang, Q., Li, W., Liu, X.S., Carroll, J. S., Jänne, O.A., Keeton, E.K., Chinnaiyan, A.M., Pienta, K.J. and Brown, M. A hierarchical network of transcription factors governs androgen receptor dependent prostate cancer growth. Mol Cell 2007;27(3):380-92.
Taplin ME, Manola J, Oh WK, Kantoff PW, Bubley GJ, Smith M, Barb D, Mantzoros C, Gelmann EP, Balk SP. (2008). A Phase II Study of mifepristone (RU-486) in castration resistant prostate cancer with correlative assessment of androgen-related hormones. BJU Int (In Press)
Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes.
Bao BY, Chuang BF, Wang Q, Sartor O, Balk SP, Brown M, Kantoff PW, Lee GS. Prostate. 2008 Jun 1;68(8):839-48.
Project 5: Project-Generated Resources
None
