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https://www.readbyqxmd.com/read/28209757/cdk4-6-therapeutic-intervention-and-viable-alternative-to-taxanes-in-crpc
#1
James P Stice, Suzanne E Wardell, John D Norris, Alexander P Yllanes, Holly M Alley, Victoria O Haney, Hannah S White, Rachid Safi, Peter S Winter, Kimberly J Cocce, Rigel J Kishton, Scott A Lawrence, Jay C Strum, Donald P McDonnell
: Resistance to second generation AR antagonists and CYP17 inhibitors in patients with castrationresistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to androgen receptor (AR) overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand binding specificity. It has been established that androgens induce cell cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6)...
February 16, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28205582/aurora-a-regulates-expression-of-ar-v7-in-models-of-castrate-resistant-prostate-cancer
#2
Dominic Jones, Martin Noble, Steve R Wedge, Craig N Robson, Luke Gaughan
Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28144969/high-levels-of-the-ar-v7-splice-variant-and-co-amplification-of-the-golgi-protein-coding-yipf6-in-ar-amplified-prostate-cancer-bone-metastases
#3
Erik Djusberg, Emma Jernberg, Elin Thysell, Irina Golovleva, Pia Lundberg, Sead Crnalic, Anders Widmark, Anders Bergh, Maria Brattsand, Pernilla Wikström
BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis...
February 1, 2017: Prostate
https://www.readbyqxmd.com/read/28129131/6bio-enhances-oligonucleotide-activity-in-cells-a-potential-combinatorial-anti-androgen-receptor-therapy-in-prostate-cancer-cells
#4
Xiaowei Zhang, Daniela Castanotto, Sangkil Nam, David Horne, Cy Stein
Approximately 15%-25% of men diagnosed with prostate cancer do not survive their disease. The American Cancer Society estimated that for the year 2016 the number of prostate cancer deaths will be 26,120. Thus, there is a critical need for novel approaches to treat this deadly disease. Using high-throughput small-molecule screening, we found that the small molecule 6-bromo-indirubin-3'-oxime (6BIO) significantly improves the targeting of antisense oligonucleotides (ASOs) delivered by gymnosis (i.e., in the absence of any transfection reagents) in both the cell cytoplasm and the nucleus...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28105499/cx4945-suppresses-the-growth-of-castration-resistant-prostate-cancer-cells-by-reducing-ar-v7-expression
#5
Chuangzhong Deng, Jieping Chen, Shengjie Guo, Yanjun Wang, Qianghua Zhou, Zaishang Li, Xingping Yang, Xingsu Yu, Zhenfeng Zhang, Fangjian Zhou, Hui Han, Kai Yao
PURPOSE: The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. METHODS: A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay...
January 19, 2017: World Journal of Urology
https://www.readbyqxmd.com/read/28104311/comprehensive-profiling-of-the-androgen-receptor-in-liquid-biopsies-from-castration-resistant-prostate-cancer-reveals-novel-intra-ar-structural-variation-and-splice-variant-expression-patterns
#6
Bram De Laere, Pieter-Jan van Dam, Tom Whitington, Markus Mayrhofer, Emanuela Henao Diaz, Gert Van den Eynden, Jean Vandebroek, Jurgen Del-Favero, Steven Van Laere, Luc Dirix, Henrik Grönberg, Johan Lindberg
BACKGROUND: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. OBJECTIVE: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy...
January 16, 2017: European Urology
https://www.readbyqxmd.com/read/28089303/practical-polling-for-prostate-cancer-ar-v7-based-treatment-selection
#7
EDITORIAL
Alastair D Lamb, Mitchell G Lawrence, Shahneen Sandhu
No abstract text is available yet for this article.
January 11, 2017: European Urology
https://www.readbyqxmd.com/read/28025139/the-rna-helicase-ddx39b-and-its-paralog-ddx39a-regulate-androgen-receptor-splice-variant-ar-v7-generation
#8
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...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27979426/nuclear-specific-ar-v7-protein-localization-is-necessary-to-guide-treatment-selection-in-metastatic-castration-resistant-prostate-cancer
#9
Howard I Scher, Ryon P Graf, Nicole A Schreiber, Brigit McLaughlin, David Lu, Jessica Louw, Daniel C Danila, Lyndsey Dugan, Ann Johnson, Glenn Heller, Martin Fleisher, Ryan Dittamore
BACKGROUND: Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. OBJECTIVE: To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi...
December 12, 2016: European Urology
https://www.readbyqxmd.com/read/27916435/analytical-validation-of-androgen-receptor-splice-variant-7-detection-in-a-clinical-laboratory-improvement-amendments-clia-laboratory-setting
#10
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/27822685/sequencing-treatment-for-castration-resistant-prostate-cancer
#11
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/27779227/prostate-cancer-exosomal-ar-v7-is-a-marker-of-hormonal-therapy-resistance
#12
Annette Fenner
No abstract text is available yet for this article.
December 2016: Nature Reviews. Urology
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
#13
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/27707886/exploitation-of-castration-resistant-prostate-cancer-transcription-factor-dependencies-by-the-novel-bet-inhibitor-abbv-075
#14
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/27699828/high-content-screening-identifies-src-family-kinases-as-potential-regulators-of-ar-v7-expression-and-androgen-independent-cell-growth
#15
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/27683042/identification-of-mir-30b-3p-and-mir-30d-5p-as-direct-regulators-of-androgen-receptor-signaling-in-prostate-cancer-by-complementary-functional-microrna-library-screening
#16
Binod Kumar, Salar Khaleghzadegan, Brian Mears, Koji Hatano, Tarana A Kudrolli, Wasim H Chowdhury, David B Yeater, Charles M Ewing, Jun Luo, William B Isaacs, Luigi Marchionni, Shawn E Lupold
The Androgen Receptor (AR) plays a key role in prostate biology and in the progression of prostate cancer (PCa) to castration resistance. The role of microRNAs (miRNAs) in aberrant AR signaling have not been fully characterized. Here we screened a library of 810 miRNA mimics to identify miRNAs that alter AR activity in complementary functional assays including protein lysate microarray (LMA) quantification of AR and PSA protein levels, AR transcriptional reporter activity, and AR-positive PCa cell viability...
8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27671337/interplay-between-cytoplasmic-and-nuclear-androgen-receptor-splice-variants-mediates-castration-resistance
#17
Yang Zhan, Guanyi Zhang, Xiaojie Wang, Yanfeng Qi, Shanshan Bai, Dongying Li, Tianfang Ma, Oliver Sartor, Erik K Flemington, Haitao Zhang, Peng Lee, Yan Dong
: Androgen receptor splice variants (AR-V) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often coexpressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL...
January 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27641787/reply-from-authors-re-emmanuel-s-antonarakis-howard-i-scher-do-patients-with-ar-v7-positive-prostate-cancer-benefit-from-novel-hormonal-therapies-it-all-depends-on-definitions-eur-urol-2017-71-4-6-unsplicing-a-conflict
#18
EDITORIAL
Julie Steinestel, Christof Bernemann, Andres J Schrader, Jochen K Lennerz
No abstract text is available yet for this article.
January 2017: European Urology
https://www.readbyqxmd.com/read/27630154/accession-of-tumor-heterogeneity-by-multiplex-transcriptome-profiling-of-single-circulating-tumor-cells
#19
Tobias M Gorges, Andra Kuske, Katharina Röck, Oliver Mauermann, Volkmar Müller, Sven Peine, Karl Verpoort, Vendula Novosadova, Mikael Kubista, Sabine Riethdorf, Klaus Pantel
BACKGROUND: Transcriptome analysis of circulating tumor cells (CTCs) holds great promise to unravel the biology of cancer cell dissemination and identify expressed genes and signaling pathways relevant to therapeutic interventions. METHODS: CTCs were enriched based on their EpCAM expression (CellSearch(®)) or by size and deformability (Parsortix(TM)), identified by EpCAM and/or pan-keratin-specific antibodies, and isolated for single cell multiplex RNA profiling...
November 2016: Clinical Chemistry
https://www.readbyqxmd.com/read/27628794/re-association-of-ar-v7-on-circulating-tumor-cells-as-a-treatment-specific-biomarker-with-outcomes-and-survival-in-castration-resistant-prostate-cancer
#20
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