Our focus during the last funding """"""""period was on molecular mechanisms driving androgen receptor (AR) activity in castration resistant prostate cancer (CRPC) and on the specific functions of AR in CRPC. We have shown that increased intratumoral androgen synthesis contributes to the reactivation of AR transcriptional activity in CRPC. This mechanism is targeted by CYP17A1 inhibitors, including the recently FDA approved drug abiraterone. Unfortunately, most patients who respond to abiraterone relapse within 1-2 years, and current data indicate that AR is active in these recurrent tumors. Additional mechanisms that enhance AR activity and drive tumor progression in CRPC are almost certainly also contributing to abiraterone resistance/relapse. Moreover, while TMPRSS2:ERG fusion and PTEN are examples of frequent genomic alterations in prostate cancer, it is becoming clear that multiple additional genomic events may be contributing in small subsets of patients, and that many of these may have therapeutic implications. This may be particularly true in advanced CRPC, and we hypothesize that a diversity of genomic alterations may be contributing to AR activation and tumor progression in CRPC and abiraterone-resistant CRPC. Our objective in Aim 1 is to identify mechanisms mediating abiraterone-resistant CRPC. During the last funding period we also demonstrated epigenetic reprogramming of AR function in CRPC. In particular, we found that AR in CRPC cells is recruited to and stimulates the expression of genes that drive cells through mitosis. Previous studies have shown that the epigenetic regulator EZH2 is up-regulated in CRPC. In recent studies we have found that EZH2 can be recruited to the cis-regulatory elements of mitotic genes targeted by AR in CRPC. Significantly, EZH2 directly up-regulates these AR targets in CRPC cells and stimulates their growth. This novel EZH2 function is dependent on its methyltransferase activity, but is not dependent on H3K27 methylation. Finally, we have found that phosphorylation of EZH2 by CDK1 alters its activity. These findings, in conjunction with our data showing that AR is also phoshorylated and activated by CDK1, indicate that a positive loop involving AR, EZH2, and CDK1 may be driving AR activity and proliferation in a subset of CRPC.
Aim 2 will test the hypothesis that EZH2 reprograms AR function in subsets of CRPC patients, and Aim 3 will assess in preclinical models and a clinical trial the efficacy of agents that suppress AR and EZH2 function through inhibiting CDK1.

Public Health Relevance

The proposed studies will build on progress made in understanding the importance of the androgen receptor in castration resistant prostate cancer to define the genetic and epigenetic mechanisms underlying progression to abiraterone resistance in patients. In addition it will explore the role of the epigenetic regulator EZH2 in castration resistance and the potential of CDK1 as a therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA090381-11A1
Application #
8554557
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
2001-04-01
Project End
2018-06-30
Budget Start
2013-09-23
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$293,784
Indirect Cost
$86,703
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Preston, Mark A; Batista, Julie L; Wilson, Kathryn M et al. (2016) Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer. J Clin Oncol 34:2705-11
Sinnott, Jennifer A; Peisch, Sam; Tyekucheva, Svitlana et al. (2016) Prognostic Utility of a New mRNA Expression Signature of Gleason Score. Clin Cancer Res :
Yang, Meng; Zu, Ke; Mucci, Lorelei A et al. (2016) Vascular morphology differentiates prostate cancer mortality risk among men with higher Gleason grade. Cancer Causes Control 27:1043-7
Thorgeirsson, Tryggvi; Jordahl, Kristina M; Flavin, Richard et al. (2016) Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort. Carcinogenesis 37:262-8
Kelly, Rachel S; Vander Heiden, Matthew G; Giovannucci, Edward et al. (2016) Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence. Cancer Epidemiol Biomarkers Prev 25:887-906
Gerrin, Sean J; Sowalsky, Adam G; Balk, Steven P et al. (2016) Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma. Prostate 76:1227-36
Liu, Xiaming; Han, Weiwei; Gulla, Sarah et al. (2016) Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. Oncotarget 7:1754-64
Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M et al. (2016) Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression. J Clin Endocrinol Metab 101:2520-7
Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng et al. (2016) Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533:547-51
Xie, Wanling; Yang, Ming; Chan, June et al. (2016) Association of genetic variations of selenoprotein genes, plasma selenium levels, and prostate cancer aggressiveness at diagnosis. Prostate 76:691-9

Showing the most recent 10 out of 217 publications