The vast majority of prostate cancers are androgen dependent, and androgen deprivation therapy (ADT) remains the standard treatment for non-organ-confined prostate cancer. Unfortunately, patients treated with ADT invariably relapse with progressive systemic prostate cancer that has been termed hormone-refractory or androgen-independent prostate cancer (AlCaP). Significantly, most cases of AlCaP are associated with high levels of androgen receptor (AR) mRNA and protein, as well as renewed expression of androgen regulated genes (such as prostate specific antigen (PSA), TMPRSS2, and the recently identified TMPRSS2/ETS fusion genes), suggesting that AR and AR-regulated genes remain critical for tumor growth in AlCaP. However, the molecular events mediating the apparent reactivation of AR transcriptional activity in AlCaP, and the critical downstream AR-regulated genes, remain to be determined. We recently reported our results using Affymetrix oligonucleotide microarrays to compare gene expression in a series of laser capture microdissected primary prostate cancer samples versus AlCaP bone marrow metastases. These studies demonstrated a high level of expression of AR mRNA in AlCaP together with renewed expression of multiple strongly AR-regulated genes, confirming substantial reactivation of AR-mediated transcription despite castrate androgen levels. With respect to potential mechanisms for this AR reactivation, we found that AlCaP samples had marked increases in enzymes that mediate androgen metabolism, suggesting that enhanced synthesis of the ligands testosterone and dihydrotestosterone (DHT) by AlCaP is one potential mechanism contributing to relapse after castration.
The Specific Aims of this Project are to:
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 Prostate cancer.
Aim 2 : Combine gene expression data from androgen-independent prostate cancer cell lines and xenografts with AR ChlP-on-chip from these cell lines to identify critical AR cooperating factors and regulated genes that may be therapeutic targets in androgen independent prostate cancer.
Aim 3 : Validate AR-regulated genes as therapeutic targets in clinical AlCaP cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090381-10
Application #
8316163
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
2013-06-30
Budget Start
2011-08-08
Budget End
2013-06-30
Support Year
10
Fiscal Year
2011
Total Cost
$271,799
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Pakula, Hubert; Linn, Douglas E; Schmidt, Daniel R et al. (2018) Protocols for Studies on TMPRSS2/ERG in Prostate Cancer. Methods Mol Biol 1786:131-151
Elfandy, Habiba; Armenia, Joshua; Pederzoli, Filippo et al. (2018) Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate. Mol Cancer Res :
Han, W; Gao, S; Barrett, D et al. (2018) Reactivation of androgen receptor-regulated lipid biosynthesis drives the progression of castration-resistant prostate cancer. Oncogene 37:710-721
Stopsack, Konrad H; Gonzalez-Feliciano, Amparo G; Peisch, Samuel F et al. (2018) A Prospective Study of Aspirin Use and Prostate Cancer Risk by TMPRSS2:ERG Status. Cancer Epidemiol Biomarkers Prev 27:1231-1233
Russo, Joshua W; Liu, Xiaming; Ye, Huihui et al. (2018) Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 438:97-104
Pettersson, Andreas; Gerke, Travis; Penney, Kathryn L et al. (2018) MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer. Cancer Epidemiol Biomarkers Prev 27:201-207
Tsang, Sabrina H; Peisch, Samuel F; Rowan, Brendan et al. (2018) Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer :
Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470
Francini, Edoardo; Gray, Kathryn P; Xie, Wanling et al. (2018) Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). Prostate 78:889-895
Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362

Showing the most recent 10 out of 261 publications