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https://www.readbyqxmd.com/read/29323792/the-retinamide-vnlg-152-inhibits-ar-ar-v7-and-mnk-eif4esignaling-pathways-to-suppress-emt-and-castration-resistant-prostate-cancer-xenograft-growth
#1
Vidya P Ramamurthy, Senthilmurugan Ramalingam, Lalji K Gediya, Vincent C O Njar
VNLG-152, a lead novel retinamide (NR) shown to suppress growth and progression in genetically diverse PCa cells via inhibition of AR signaling and eIF4E translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration resistant prostate cancer (CRPC) growth and metastatic phenotype in CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% respectively (P = 0.001), vs. vehicle with no host toxicity...
January 11, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29319382/ctc-derived-ar-v7-detection-as-a-prognostic-and-predictive-biomarker-in-advanced-prostate-cancer
#2
Diogo A Bastos, Emmanuel S Antonarakis
Prostate cancer is a highly heterogeneous disease, with remarkably different prognosis across all stages. Increased circulating tumor cell (CTC) count (≥ 5) using the CellSearch assay has been identified as one of the markers that can be used to predict survival, with added value beyond currently available prognostic factors. Recently, androgen receptor splice variant 7 (AR-V7) detection has been associated with worse outcomes for patients with castration-resistant prostate cancer (CRPC) treated with novel androgen receptor-signaling (ARS) inhibitors such as abiraterone and enzalutamide but not taxane chemotherapies...
January 10, 2018: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/29301749/in-situ-detection-and-quantification-of-ar-v7-ar-fl-psa-and-kras-point-mutations-in-circulating-tumor-cells
#3
Amin El-Heliebi, Claudia Hille, Navya Laxman, Jessica Svedlund, Christoph Haudum, Erkan Ercan, Thomas Kroneis, Shukun Chen, Maria Smolle, Christopher Rossmann, Tomasz Krzywkowski, Annika Ahlford, Evangelia Darai, Gunhild von Amsberg, Winfried Alsdorf, Frank König, Matthias Löhr, Inge de Kruijff, Sabine Riethdorf, Tobias M Gorges, Klaus Pantel, Thomas Bauernhofer, Mats Nilsson, Peter Sedlmayr
BACKGROUND: Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs...
January 4, 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29301747/an-rna-based-digital-circulating-tumor-cell-signature-is-predictive-of-drug-response-and-early-dissemination-in-prostate-cancer
#4
David T Miyamoto, Richard J Lee, Mark Kalinich, Joseph LiCausi, Yu Zheng, Tianqi Chen, John D Milner, Erin Emmons, Uyen Ho, Katherine Broderick, Erin Silva, Sarah Javaid, Tanya Todorova Kwan, Xin Hong, Douglas M Dahl, Francis J McGovern, Jason A Efstathiou, Matthew R Smith, Lecia V Sequist, Ravi Kapur, Chin-Lee Wu, Shannon L Stott, David T Ting, Anita Giobbie-Hurder, Mehmet Toner, Shyamala Maheswaran, Daniel A Haber
Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTCs) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 metastatic castration-resistant prostate cancer patients treated with first-line abiraterone, pretreatment elevation of the digital CTCM Score identifies a high risk population with poor overall survival (HR 6...
January 4, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29258679/role-of-androgen-receptor-variants-in-prostate-cancer-report-from-the-2017-mission-androgen-receptor-variants-meeting
#5
Jun Luo, Gerhardt Attard, Steven P Balk, Charlotte Bevan, Kerry Burnstein, Laura Cato, Artem Cherkasov, Johann S De Bono, Yan Dong, Allen C Gao, Martin Gleave, Hannelore Heemers, Mayuko Kanayama, Ralf Kittler, Joshua M Lang, Richard J Lee, Christopher J Logothetis, Robert Matusik, Stephen Plymate, Charles L Sawyers, Luke A Selth, Howard Soule, Wayne Tilley, Nancy L Weigel, Amina Zoubeidi, Scott M Dehm, Ganesh V Raj
CONTEXT: Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). OBJECTIVE: Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. EVIDENCE ACQUISITION: The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF)...
December 16, 2017: European Urology
https://www.readbyqxmd.com/read/29249800/dbc1-promotes-castration-resistant-prostate-cancer-by-positively-regulating-dna-binding-and-stability-of-ar-v7
#6
Sue Jin Moon, Byong Chang Jeong, Hwa Jin Kim, Joung Eun Lim, Ghee Young Kwon, Jeong Hoon Kim
Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression...
December 18, 2017: Oncogene
https://www.readbyqxmd.com/read/29243324/validation-of-histone-deacetylase-3-as-a-therapeutic-target-in-castration-resistant-prostate-cancer
#7
Abigail B McLeod, James P Stice, Suzanne E Wardell, Holly M Alley, Ching-Yi Chang, Donald P McDonnell
BACKGROUND: Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclinical data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC...
December 15, 2017: Prostate
https://www.readbyqxmd.com/read/29198908/overexpression-of-nuclear-ar-v7-protein-in-primary-prostate-cancer-is-an-independent-negative-prognostic-marker-in-men-with-high-risk-disease-receiving-adjuvant-therapy
#8
Xin Chen, Christof Bernemann, Yuri Tolkach, Martina Heller, Cathleen Nientiedt, Michael Falkenstein, Esther Herpel, Maximilian Jenzer, Carsten Grüllich, Dirk Jäger, Holger Sültmann, Anette Duensing, Sven Perner, Marcus V Cronauer, Carsten Stephan, Jürgen Debus, Andres Jan Schrader, Glen Kristiansen, Markus Hohenfellner, Stefan Duensing
BACKGROUND: Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be. METHODS: An anti-AR-V7 antibody was first validated in a training set of prostate cancer specimens by a comparison of AR-V7 protein to AR-V7 mRNA expression...
November 29, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/29179452/novel-galeterone-analogs-act-independently-of-ar-and-ar-v7-for-the-activation-of-the-unfolded-protein-response-and-induction-of-apoptosis-in-the-cwr22rv1-prostate-cancer-cell-model
#9
David J McCarty, Weiliang Huang, Maureen A Kane, Puranik Purushottamachar, Lalji K Gediya, Vincent C O Njar
The androgen receptor (AR) has long been the primary target for the treatment of prostate cancer (PC). Despite continuous efforts to block AR activity through ligand depletion, AR antagonism, AR depletion and combinations thereof, advanced PC tumors remain resilient. Herein, we evaluate two galeterone analogs, VNPT-178 and VNLG-74A, in PC cell models of diverse androgen and AR dependence attempting to delineate their mechanisms of action and potential clinical utility. Employing basic biochemical techniques, we determined that both analogs have improved antiproliferative and anti-AR activities compared to FDA-approved abiraterone and enzalutamide...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29170762/clinical-utility-of-clia-grade-ar-v7-testing-in-patients-with-metastatic-castration-resistant-prostate-cancer
#10
Mark C Markowski, John L Silberstein, James R Eshleman, Mario A Eisenberger, Jun Luo, Emmanuel S Antonarakis
Purpose: A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments-certified laboratory at Johns Hopkins University. Methods: We contacted ordering providers of the first 150 consecutive tests by using a questionnaire-based survey to determine how the results of AR-V7 testing were used to influence clinical practice...
2017: JCO Precision Oncology
https://www.readbyqxmd.com/read/29162351/refining-the-assessment-and-implications-of-ar-v7-in-castrate-resistant-prostate-cancer
#11
EDITORIAL
Megan Crumbaker, Richard Savdie, Anthony M Joshua
No abstract text is available yet for this article.
November 18, 2017: European Urology
https://www.readbyqxmd.com/read/29134684/enhanced-radiosensitization-of-enzalutamide-via-schedule-dependent-administration-to-androgen-sensitive-prostate-cancer-cells
#12
Maryam Ghashghaei, Miltiadis Paliouras, Mitra Heravi, Hamed Bekerat, Mark Trifiro, Tamim M Niazi, Thierry Muanza
BACKGROUND: Prostate cancer (PCa) is a progressive disease and the most diagnosed cancer in men. The current standard of care for high-risk localized PCa is a combination of androgen deprivation therapy (ADT) and radiation (XRT). The majority of these patients however become resistant due to incomplete responses to ADT as a result of selective cells maintaining androgen receptor (AR) activity. Improvement can be made if increasing radiosensitivity is realized. Therefore, the aim of this study is to investigate the efficacy of the next-generation PCa drug Enzalutamide (ENZA), as a radiosensitizer in XRT therapy...
November 14, 2017: Prostate
https://www.readbyqxmd.com/read/29129398/genomic-markers-in-prostate-cancer-decision-making
#13
REVIEW
Vito Cucchiara, Matthew R Cooperberg, Marc Dall'Era, Daniel W Lin, Francesco Montorsi, Jack A Schalken, Christopher P Evans
CONTEXT: Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed. OBJECTIVE: This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumors, and facilitate the selection of therapies in patients with advanced disease...
November 9, 2017: European Urology
https://www.readbyqxmd.com/read/29126837/antiandrogens-reduce-intratumoral-androgen-concentrations-and-induce-androgen-receptor-expression-in-castration-resistant-prostate-cancer-xenografts
#14
Matias Knuuttila, Arfa Mehmood, Riikka Huhtaniemi, Emrah Yatkin, Merja R Häkkinen, Riikka Oksala, Teemu D Laajala, Henrik Ryberg, David J Handelsman, Tero Aittokallio, Seppo Auriola, Claes Ohlsson, Asta Laiho, Laura L Elo, Petra Sipilä, Sari I Mäkelä, Matti Poutanen
The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0...
January 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29110173/combination-treatment-with-docetaxel-and-histone-deacetylase-inhibitors-downregulates-androgen-receptor-signaling-in-castration-resistant-prostate-cancer
#15
Sang Eun Park, Ha-Gyeong Kim, Dong Eun Kim, Yoo Jung Jung, Yunlim Kim, Seong-Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Choung-Soo Kim
Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting...
November 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29076496/androgen-receptor-splice-variant-7-positive-prostate-cancer-a-novel-molecular-subtype-with-markedly-worse-androgen-deprivation-therapy-outcomes-in-newly-diagnosed-patients
#16
Heng Li, Zhize Wang, Wei Xiao, Libin Yan, Wei Guan, Zhiquan Hu, Lily Wu, Qihong Huang, Ji Wang, Hua Xu, Xu Zhang, Zhangqun Ye
Androgen-deprivation therapy has been the standard treatment for metastatic and locally advanced prostate cancer, but the majority of patients will progress to castration-resistant prostate cancer within 2-3 years. Unlike the case in breast cancer, no clinically validated biomarker has been used to predict the outcomes of androgen-deprivation therapy. To evaluate androgen-receptor splice variant-7 (AR-V7) detection in newly diagnosed advanced prostate cancer and describe the distinctive prognosis of this novel molecular subtype, this study retrospectively enrolled 168 newly diagnosed prostate cancer patients from 2003 to 2015 who received androgen-deprivation therapy...
October 27, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29071394/-study-on-the-prediction-of-ar-v7-and-ctc-circulation-in-patients-with-metastatic-castration-resistant-prostate-cancer-mcrpc-correlation-between-common-clinical-outcome-parameters-rpfs-os-ctc-changes-and-ar-v7-status-androgen-receptor-splice-variant-7-in-patients
#17
https://www.readbyqxmd.com/read/28928128/targeting-a-single-alternative-polyadenylation-site-coordinately-blocks-expression-of-androgen-receptor-mrna-splice-variants-in-prostate-cancer
#18
Jamie L Van Etten, Michael Nyquist, Yingming Li, Rendong Yang, Yeung Ho, Rachel Johnson, Olivia Ondigi, Daniel F Voytas, Christine Henzler, Scott M Dehm
Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant-specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3...
October 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28901514/multimodal-actions-of-the-phytochemical-sulforaphane-suppress-both-ar-and-ar-v7-in-22rv1-cells-advocating-a-potent-pharmaceutical-combination-against-castration-resistant-prostate-cancer
#19
Namrata Khurana, Hogyoung Kim, Partha K Chandra, Sudha Talwar, Pankaj Sharma, Asim B Abdel-Mageed, Suresh C Sikka, Debasis Mondal
Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1)...
November 2017: Oncology Reports
https://www.readbyqxmd.com/read/28866255/novel-junction-specific-and-quantifiable-in-situ-detection-of-ar-v7-and-its-clinical-correlates-in-metastatic-castration-resistant-prostate-cancer
#20
Yezi Zhu, Adam Sharp, Courtney M Anderson, John L Silberstein, Maritza Taylor, Changxue Lu, Pei Zhao, Angelo M De Marzo, Emmanuel S Antonarakis, Mindy Wang, Xingyong Wu, Yuling Luo, Nan Su, Daniel Nava Rodrigues, Ines Figueiredo, Jonathan Welti, Emily Park, Xiao-Jun Ma, Ilsa Coleman, Colm Morrissey, Stephen R Plymate, Peter S Nelson, Johann S de Bono, Jun Luo
BACKGROUND: Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. OBJECTIVE: To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification...
August 30, 2017: European Urology
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