The molecular basis of prostate cancer is becoming increasingly elucidated as the genetic abnormalities underlying the disease are identified. Most prominent among these is the androgen receptor (AR), which for decades has been known to be essential for the survival of prostate cancer cells. However, because transcription factors (including AR) are generally considered 'undruggable', pharmacological approaches to modulating AR activity have been limited, focusing on blocking ligand binding to AR, and hormonally diminishing the body's production of androgens. While tumors initially respond to such androgen deprivation therapy, recurrence inevitably occurs. New approaches to modulating AR activity are therefore needed. Similarly, the recently identified mutations in the ETS family of transcription factors observed in as many as 70% of prostate cancers call for a novel approach to pharmacologically inhibiting the activity of these mutant oncoproteins. During the prior funding cycle, we developed a novel, gene expression-based chemical screening method (GE-HTS), and applied it to the discovery of AR-modulating small molecules. Most prominent among the hits that emerged from that screen were a group of structurally unique natural products that we demonstrated were functioning as novel HSP90 inhibitors. Based on these preliminary findings, we propose the following Specific Aims:
Aim 1. Test the hypothesis that HSP90 inhibition will abrogate AR function and result in clinical responses in patients with advanced prostate cancer.
Aim 2. Develop a signature of TMPRSS2/ERG activity.
Aim 3. Screen small molecule libraries to identify compounds capable of modulating the TMPRSS2/ERG signature.
Aim 4. Validate the hits emerging from the TMPRSS2/ERG GE-HTS screen.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
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