The mechanisms underlying prostate cancer progression from androgen dependent to castration resistant prostate cancer (CRPC), as well as those mediating resistance to therapies that target the residual androgen receptor (AR) signaling in CRPC including second generation AR antagonists such as enzalutamide have not been fully elucidated. Work from several groups including our own has highlighted the continued dependence of CRPC on AR and has implicated EZH2 as an additional oncogenic driver involved in AR reprogramming in CRPC. In studies accomplished during the current funding period we have explored EZH2 as a target in models of CRPC and have demonstrated that catalytic EZH2 inhibitors have activity in these models. The goal of this proposal is to leverage the novel genome-scale CRISPR/Cas9 and ORF screening technology to identify the essential genes and their functions that underlie the hormone independence and sensitivity or resistance to EZH2 inhibitors, AR antagonists, and other targeted agents in CRPC. In addition, in collaboration with the Freedman lab we will use CRISPR/Cas9 editing of cis-regulatory elements to explore in detail the function of a novel somatically acquired transcriptional enhancer in controlling the expression of the AR gene itself in CRPC. We will also define the essential genes in models of CRPC driven by ARv7 and other AR mutants and variants in collaboration with Project 2. Finally, we will perform CRISPR and ORF screens to identify potential new synthetic lethal combinations and mechanisms of resistance including to a set of novel kinase inhibitors in collaboration with the Project 3.
Despite effective androgen ablation and anti-androgen therapies, the majority of advanced prostate cancers progress to castration resistance and ultimately to anti-androgen resistance. The objective of this research project is to leverage novel CRISPR/Cas9 and ORF genome-wide screening technologies to identify the factors mediating CRPC progression and resistance to anti-androgen therapy in order to find new therapeutic targets.
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|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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