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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-M (M1))
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Dana-Farber Cancer Institute
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Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai et al. (2015) Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 21:1273-80
Labbé, D P; Zadra, G; Ebot, E M et al. (2015) Role of diet in prostate cancer: the epigenetic link. Oncogene 34:4683-91
Sowalsky, Adam G; Xia, Zheng; Wang, Liguo et al. (2015) Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106
Penney, Kathryn L; Sinnott, Jennifer A; Tyekucheva, Svitlana et al. (2015) Association of prostate cancer risk variants with gene expression in normal and tumor tissue. Cancer Epidemiol Biomarkers Prev 24:255-60
Yu, Ziyang; Chen, Sen; Sowalsky, Adam G et al. (2014) Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res 20:1590-600
Crowe, Francesca L; Appleby, Paul N; Travis, Ruth C et al. (2014) Circulating fatty acids and prostate cancer risk: individual participant meta-analysis of prospective studies. J Natl Cancer Inst 106:
Cato, Laura; Neeb, Antje; Brown, Myles et al. (2014) Control of steroid receptor dynamics and function by genomic actions of the cochaperones p23 and Bag-1L. Nucl Recept Signal 12:e005
Sun, T; Wang, X; He, H H et al. (2014) MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene 33:2790-800
Priolo, Carmen; Pyne, Saumyadipta; Rose, Joshua et al. (2014) AKT1 and MYC induce distinctive metabolic fingerprints in human prostate cancer. Cancer Res 74:7198-204
Kissick, Haydn T; Sanda, Martin G; Dunn, Laura K et al. (2014) Immunization with a peptide containing MHC class I and II epitopes derived from the tumor antigen SIM2 induces an effective CD4 and CD8 T-cell response. PLoS One 9:e93231

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