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Androgen receptor splice variants

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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/29249800/dbc1-promotes-castration-resistant-prostate-cancer-by-positively-regulating-dna-binding-and-stability-of-ar-v7
#4
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
#5
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/29228299/development-of-cell-penetrating-bispecific-antibodies-targeting-the-n-terminal-domain-of-androgen-receptor-for-prostate-cancer-therapy
#6
Nancy L Goicochea, Maria Garnovskaya, Mary G Blanton, Grace Chan, Richard Weisbart, Michael B Lilly
Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody...
December 1, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29214142/molecular-mechanisms-of-enzalutamide-resistance-in-prostate-cancer
#7
REVIEW
Zoran Culig
Purpose of Review: Compensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous...
2017: Current Molecular Biology Reports
https://www.readbyqxmd.com/read/29209770/androgen-and-estrogen-sensitivity-of-bird-song-a-comparative-view-on-gene-regulatory-levels
#8
REVIEW
Carolina Frankl-Vilches, Manfred Gahr
Singing of songbirds is sensitive to testosterone and its androgenic and estrogenic metabolites in a species-specific way. The hormonal effects on song pattern are likely mediated by androgen receptors (AR) and estrogen receptor alpha (ERα), ligand activated transcription factors that are expressed in neurons of various areas of the songbirds' vocal control circuit. The distribution of AR in this circuit is rather similar between species while that of ERα is species variant and concerns a key vocal control area, the HVC (proper name)...
December 6, 2017: Journal of Comparative Physiology. A, Neuroethology, Sensory, Neural, and Behavioral Physiology
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
#9
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/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/29170510/whole-blood-stabilization-for-the-microfluidic-isolation-and-molecular-characterization-of-circulating-tumor-cells
#11
Keith H K Wong, Shannon N Tessier, David T Miyamoto, Kathleen L Miller, Lauren D Bookstaver, Thomas R Carey, Cleo J Stannard, Vishal Thapar, Eric C Tai, Kevin D Vo, Erin S Emmons, Haley M Pleskow, Rebecca D Sandlin, Lecia V Sequist, David T Ting, Daniel A Haber, Shyamala Maheswaran, Shannon L Stott, Mehmet Toner
Precise rare-cell technologies require the blood to be processed immediately or be stabilized with fixatives. Such restrictions limit the translation of circulating tumor cell (CTC)-based liquid biopsy assays that provide accurate molecular data in guiding clinical decisions. Here we describe a method to preserve whole blood in its minimally altered state by combining hypothermic preservation with targeted strategies that counter cooling-induced platelet activation. Using this method, whole blood preserved for up to 72 h can be readily processed for microfluidic sorting without compromising CTC yield and viability...
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29147733/-inhibitors-of-the-androgen-receptor-n%C3%A2-terminal-domain-therapies-targeting-the-achilles-heel-of-various-androgen-receptor-molecules-in-advanced-prostate-cancer
#12
REVIEW
M C Hupe, A Offermann, F Perabo, C Chandhasin, S Perner, A S Merseburger, M V Cronauer
Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR...
November 16, 2017: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/29126837/antiandrogens-reduce-intratumoral-androgen-concentrations-and-induce-androgen-receptor-expression-in-castration-resistant-prostate-cancer-xenografts
#13
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
#14
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/29104096/n-terminal-truncations-in-sex-steroid-receptors-and-rapid-steroid-actions
#15
Derek A Schreihofer, Phong Duong, Rebecca L Cunningham
Sex steroid receptors act as ligand activated nuclear transcription factors throughout the body, including the brain. However, post-translational modification of these receptors can direct them to extranuclear sites, including the plasma membrane, where they are able to initiate rapid signaling. Because of the conserved domain structure of these receptors, alternative exon splicing can result in proteins with altered nuclear and extranuclear actions. Although much attention has focused on internal and C-terminal splice variants, both estrogen and androgen receptors undergo N-terminal truncations, as well...
November 9, 2017: Steroids
https://www.readbyqxmd.com/read/29101113/treatment-of-advanced-prostate-cancer-a-review-of-current-therapies-and-future-promise
#16
Semini Sumanasuriya, Johann De Bono
Despite many recent advances in the therapy for metastatic castration-resistant prostate cancer (mCRPC), the disease remains incurable, although men suffering from this disease are living considerably longer. In this review, we discuss the current treatment options available for this disease, such as taxane-based chemotherapy, the novel hormone therapies abiraterone and enzalutamide, and treatments such as radium-223 and sipuleucel-T. We also highlight the need for ongoing research in this field, because, despite numerous recent advances, the prognosis for mCRPC remains poor...
November 3, 2017: Cold Spring Harbor Perspectives in Medicine
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
#17
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
#18
https://www.readbyqxmd.com/read/29059155/reactivation-of-androgen-receptor-regulated-lipid-biosynthesis-drives-the-progression-of-castration-resistant-prostate-cancer
#19
W Han, S Gao, D Barrett, M Ahmed, D Han, J A Macoska, H H He, C Cai
Androgen receptor (AR) is a transcriptional activator that, in prostate cells, stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen-deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/28978635/novel-selective-agents-for-the-degradation-of-androgen-receptor-variants-to-treat-castration-resistant-prostate-cancer
#20
Suriyan Ponnusamy, Christopher C Coss, Thirumagal Thiyagarajan, Kate Watts, Dong-Jin Hwang, Yali He, Luke A Selth, Iain J McEwan, Charles B Duke, Jayaprakash Pagadala, Geetika Singh, Robert W Wake, Christopher Ledbetter, Wayne D Tilley, Tudor Moldoveanu, James T Dalton, Duane D Miller, Ramesh Narayanan
Androgen receptor (AR) mediates the growth of prostate cancer throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced prostate cancer requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARD) that markedly reduce the activity of wild-type and splice variant isoforms of AR at submicromolar doses...
November 15, 2017: Cancer Research
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