Our overall objective has been to dissect transcriptional activation by androgen receptor (AR) and AR splice variants, and mechanisms driving this activity in prostate cancer (PCa) that becomes resistant to second generation AR targeted therapies including abiraterone and enzalutamide. We recently found that AR recruits protein phosphatase 1 (PP1?), which can then dephosphorylate CDK9 and mobilize the P-TEFb complex.
In Aim 1 we focus on identification of the PP1 regulatory protein that interacts with the AR ligand binding domain (independently of androgen) that mediates this interaction, and on determining whether/how the AR-V7 splice variant mediates PP1? recruitment and subsequent P-TEFb mobilization. Our previous and current studies also indicate that phosphorylation of S81 in the AR N-terminal domain (NTD) plays a major role in driving transcription, and is a hub for a positive feedback loop that may amplify AR activity at low androgen levels or in the presence of AR antagonists. Therefore, Aim 2 focuses on identification of coactivator interactions that are directly or indirectly regulated by S81 phosphorylation, the role of S81 phosphorylation in AR-V7 activity, and the therapeutic potential of CDK9 inhibitors.
Aim 3 then focuses further on AR splice variants. While AR splice variant homodimers can drive transcription, evidence from others and us indicate that heterodimers between AR-FL and AR splice variants play a major role. Therefore, we will test the hypothesis that AR-FL/V7 heterodimers are the major mediators of AR activity in enzalutamide-resistant PCa models. We then will focus on the role of the LBD in these heterodimers, and whether they it may still be a therapeutic target. Finally, we will identify mechanisms in addition to increased expression that appear to be enhancing AR-V7 activity in enzalutamide-resistant PCa cells.
The Specific Aims are 1) Determine the molecular basis for PP1? recruitment by AR full length and splice variants, 2) Determine the function of AR S81 phosphorylation in driving AR full length and splice variants, 3) Identify mechanisms through which AR-V7 drives AR activity in ENZ-resistant models.
Our overall objective is to understand the molecular basis for persistent androgen receptor (AR) activity in prostate cancer (PCa) that becomes resistant to current AR targeted therapies including abiraterone and enzalutamide. Aims 1 and 2 will test the hypothesis that AR recruitment of protein phosphatase 1, with subsequent mobilization/recruitment of CDK9 and phosphorylation of S81 in the AR N-terminal domain, generates a positive feedback loop that drives AR activity in therapy-resistant PCa, and will assess the CDK9 inhibition as a therapy. Aim 3 will test the hypothesis that heterodimerization of AR splice variants with full length AR is critical for their action, and identify potential novel therapies targeting these heterodimers.
|Beshiri, Michael L; Tice, Caitlin M; Tran, Crystal et al. (2018) A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. Clin Cancer Res 24:4332-4345|
|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|
|Mostaghel, Elahe A (2018) Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer. Clin Cancer Res :|
|Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C (2018) The potential of AR-V7 as a therapeutic target. Expert Opin Ther Targets 22:201-216|
|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|
|Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19|
|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|
|Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730|
|Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735|
|Penning, Trevor M (2018) Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer. Vitam Horm 108:309-331|
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