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Androgen receptor splice variants

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https://www.readbyqxmd.com/read/28077788/androgen-receptor-splice-variants-and-prostate-cancer-from-bench-to-bedside
#1
REVIEW
Kristine M Wadosky, Shahriar Koochekpour
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28036278/a-novel-nonsense-mutation-in-androgen-receptor-confers-resistance-to-cyp17-inhibitor-treatment-in-prostate-cancer
#2
Dong Han, Shuai Gao, Kevin Valencia, Jude Owiredu, Wanting Han, Eric de Waal, Jill A Macoska, Changmeng Cai
The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035996/novel-nine-exon-ar-transcripts-exon-1-exon-1b-exons-2-8-in-normal-and-cancerous-breast-and-prostate-cells
#3
Dong Gui Hu, Ross A McKinnon, Julie-Ann Hulin, Peter I Mackenzie, Robyn Meech
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b...
December 27, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28025139/the-rna-helicase-ddx39b-and-its-paralog-ddx39a-regulate-androgen-receptor-splice-variant-ar-v7-generation
#4
Daisuke Nakata, Shoichi Nakao, Kazuhide Nakayama, Shinsuke Araki, Yusuke Nakayama, Samuel Aparicio, Takahito Hara, Atsushi Nakanishi
Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation...
December 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27959342/ailanthone-targets-p23-to-overcome-mdv3100-resistance-in-castration-resistant-prostate-cancer
#5
Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours...
December 13, 2016: Nature Communications
https://www.readbyqxmd.com/read/27916435/analytical-validation-of-androgen-receptor-splice-variant-7-detection-in-a-clinical-laboratory-improvement-amendments-clia-laboratory-setting
#6
Parvez M Lokhandwala, Stacy L Riel, Lisa Haley, Changxue Lu, Yan Chen, John Silberstein, Yezi Zhu, Gang Zheng, Ming-Tseh Lin, Christopher D Gocke, Alan W Partin, Emmanuel S Antonarakis, Jun Luo, James R Eshleman
Patients with castration-resistant prostate cancer (CRPC) often are treated with drugs that target the androgen receptor (AR) ligand-binding domain. Constitutively active AR splice variant 7 (AR-V7) lacks the ligand-binding domain and, if detected in circulating tumor cells, may be associated with resistance to these agents. We validated an AR-V7 assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Circulating tumor cells were isolated, and mRNA was reverse-transcribed into cDNA...
January 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27915475/how-precisely-can-prostate-cancer-be-managed
#7
REVIEW
Liyan Zhuang, Matthew T Johnson
Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2- ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy...
November 2016: International Neurourology Journal
https://www.readbyqxmd.com/read/27903893/identification-of-a-novel-k311-ubiquitination-site-critical-for-androgen-receptor-transcriptional-activity
#8
Urszula L McClurg, David M W Cork, Steven Darby, Claudia A Ryan-Munden, Sirintra Nakjang, Leticia Mendes Côrtes, Achim Treumann, Luke Gaughan, Craig N Robson
The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27843207/chemotherapy-options-in-castration-resistant-prostate-cancer
#9
REVIEW
Benjamin A Teply, Ralph J Hauke
INTRODUCTION: The treatment landscape for patients with metastatic castration-resistant prostate cancer (CRPC) is evolving, with recent approvals of immune therapy, novel hormonal therapy, and bone-targeted therapy. Chemotherapy remains an essential component of the armamentarium. Herein, we review current chemotherapy options for patients with CRPC and discuss future challenges. METHODS: We reviewed literature for chemotherapy agents in prostate cancer, with special attention to the evidence for efficacy of the currently approved agents...
October 2016: Indian Journal of Urology: IJU: Journal of the Urological Society of India
https://www.readbyqxmd.com/read/27822685/sequencing-treatment-for-castration-resistant-prostate-cancer
#10
REVIEW
Catherine E Handy, Emmanuel S Antonarakis
Prostate cancer is the most common non-cutaneous cancer diagnosed in men and the second leading cause of male cancer deaths in the USA. While most cases are diagnosed in early stages, some will present as or progress to metastatic disease and eventually castration-resistant prostate cancer (mCRPC) which has a mortality rate exceeding 50 %. There are currently six approved systemic life-prolonging therapies for use in mCRPC, yet little data to guide sequencing. Clinical factors, including the presence or absence of symptoms and the presence or absence of visceral metastases, should help determine the best therapeutic choice at each treatment node...
December 2016: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/27749325/androgen-receptor-and-beyond-targeting-androgen-signaling-in-castration-resistant-prostate-cancer
#11
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
https://www.readbyqxmd.com/read/27733296/the-detection-of-androgen-receptor-splice-variant-7-in-plasma-derived-exosomal-rna-strongly-predicts-resistance-to-hormonal-therapy-in-metastatic-prostate-cancer-patients
#12
Marzia Del Re, Elisa Biasco, Stefania Crucitta, Lisa Derosa, Eleonora Rofi, Cinzia Orlandini, Mario Miccoli, Luca Galli, Alfredo Falcone, Guido W Jenster, Ron H van Schaik, Romano Danesi
BACKGROUND: The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. OBJECTIVE: To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA...
August 26, 2016: European Urology
https://www.readbyqxmd.com/read/27725309/androgen-receptor-variation-affects-prostate-cancer-progression-and-drug-resistance
#13
REVIEW
Edel McCrea, Tristan M Sissung, Douglas K Price, Cindy H Chau, William D Figg
Significant therapeutic progress has been made in treating prostate cancer in recent years. Drugs such as enzalutamide, abiraterone, and cabazitaxel have expanded the treatment armamentarium, although it is not completely clear which of these drugs are the most-effective option for individual patients. Moreover, such advances have been tempered by the development of therapeutic resistance. The purpose of this review is to summarize the current literature pertaining to the biochemical effects of AR variants and their consequences on prostate cancer therapies at both the molecular level and in clinical treatment...
December 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27717544/targeting-prostate-cancer-with-compounds-possessing-dual-activity-as-androgen-receptor-antagonists-and-hdac6-inhibitors
#14
Pradeep S Jadhavar, Sreekanth A Ramachandran, Eduardo Riquelme, Ashu Gupta, Kevin P Quinn, Devleena Shivakumar, Soumya Ray, Dnyaneshwar Zende, Anjan K Nayak, Sandeep K Miglani, Balaji D Sathe, Mohd Raja, Olivia Farias, Ivan Alfaro, Sebastián Belmar, Javier Guerrero, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Jeffrey N Lindquist, Roopa Rai
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios...
October 4, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27707886/exploitation-of-castration-resistant-prostate-cancer-transcription-factor-dependencies-by-the-novel-bet-inhibitor-abbv-075
#15
Emily J Faivre, Denise Wilcox, Xiaoyu Lin, Paul Hessler, Maricel Torrent, Wei He, Tamar Uziel, Daniel H Albert, Keith McDaniel, Warren Kati, Yu Shen
: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075...
October 5, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27702752/emerging-data-on-androgen-receptor-splice-variants-in-prostate-cancer
#16
REVIEW
Subing Cao, Yang Zhan, Yan Dong
Androgen receptor splice variants are alternatively spliced variants of androgen receptor, which are C-terminally truncated and lack the canonical ligand-binding domain. Accumulating evidence has indicated a significant role of androgen receptor splice variants in mediating resistance of castration-resistant prostate cancer to current therapies and in predicting therapeutic responses. As such, there is an urgent need to target androgen receptor splicing variants for more effective treatment of castration-resistant prostate cancer...
December 2016: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27699828/high-content-screening-identifies-src-family-kinases-as-potential-regulators-of-ar-v7-expression-and-androgen-independent-cell-growth
#17
Adam T Szafran, Cliff Stephan, Michael Bolt, Maureen G Mancini, Marco Marcelli, Michael A Mancini
BACKGROUND: AR-V7 is an androgen receptor (AR) splice variant that lacks the ligand-binding domain and is isolated from prostate cancer cell lines. Increased expression of AR-V7 is associated with the transition from hormone-sensitive prostate cancer to more advanced castration-resistant prostate cancer (CRPC). Due to the loss of the ligand-binding domain, AR-V7 is not responsive to traditional AR-targeted therapies, and the mechanisms that regulate AR-V7 are still incompletely understood...
January 2017: Prostate
https://www.readbyqxmd.com/read/27694897/systematic-and-functional-characterization-of-novel-androgen-receptor-variants-arising-from-alternative-splicing-in-the-ligand-binding-domain
#18
T Uo, H Dvinge, C C Sprenger, R K Bradley, P S Nelson, S R Plymate
The presence of intact ligand-binding domain (LBD) ensures the strict androgen-dependent regulation of androgen receptor (AR): binding of androgen induces structural reorganization of LBD resulting in release of AR from HSP90, suppression of nuclear export which otherwise dominates over import and nuclear translocation of AR as a transcription factor. Thus, loss or defects of the LBD abolish constraint from un-liganded LBD as exemplified by constitutively active AR variants (AR-Vs), which are associated with emerging resistance mechanism to anti-AR therapy in castration-resistant prostate cancer (mCRPC)...
October 3, 2016: Oncogene
https://www.readbyqxmd.com/read/27683182/a-phase-ii-trial-of-abiraterone-combined-with-dutasteride-for-men-with-metastatic-castration-resistant-prostate-cancer
#19
Rana R McKay, Lillian Werner, Elahe A Mostaghel, Rosina Lis, Olga Voznesensky, Zhenwei Zhang, Brett T Marck, Alvin M Matsumoto, Liran Domachevsky, Katherine A Zukotynski, Manoj Bhasin, Glenn J Bubley, Bruce Montgomery, Philip W Kantoff, Steven P Balk, Mary-Ellen Taplin
PURPOSE: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. EXPERIMENTAL DESIGN: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27682980/regulation-of-pcgem1-by-p54-nrb-in-prostate-cancer
#20
Tsui-Ting Ho, Jianguo Huang, Nanjiang Zhou, Ziqiang Zhang, Pratirodh Koirala, Xinchun Zhou, Fangting Wu, Xianfeng Ding, Yin-Yuan Mo
PCGEM1 is a long non-coding RNA (lncRNA) that is often upregulated in prostate cancer. However, little is known how PCGEM1 is regulated. In the present study, we show transcriptional regulation of PCGEM1 in response to androgen deprivation by p54/nrb. While ectopic expression of p54/nrb increases, suppression of p54/nrb by RNAi or knockout (KO) reduces PCGEM1. Moreover, rescue experiments indicate that re-expression of p54/nrb in KO cells restores the ability to induce PCGEM1, leading to upregulation of the androgen receptor splice variant AR3 which has been shown to play a role in castration resistance...
September 29, 2016: Scientific Reports
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