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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
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
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...
October 4, 2016: Prostate
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...
September 24, 2016: Oncotarget
Yang Zhan, Guanyi Zhang, Xiaojie Wang, Yangfeng Qi, Dongyi Li, Shanshan Bai, Tianfang Ma, Erik K Flemington, Haitao Zhang, Oliver Sartor, Peng Lee, Yan Dong
: Androgen receptor splice variants (AR-Vs) 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 co-expressed 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...
September 26, 2016: Molecular Cancer Research: MCR
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™), identified by EpCAM and/or pan-keratin-specific antibodies, and isolated for single cell multiplex RNA profiling. RESULTS: Distinct breast and prostate CTC expression signatures could be discriminated from RNA profiles of leukocytes...
September 14, 2016: Clinical Chemistry
Sergey A Dyshlovoy, Katharina Otte, Winfried H Alsdorf, Jessica Hauschild, Tobias Lange, Simone Venz, Christiane K Bauer, Robert Bähring, Kerstin Amann, Ramin Mandanchi, Udo Schumacher, Jennifer Schröder-Schwarz, Tatyana N Makarieva, Alla G Guzii, Kseniya M Tabakmakher, Sergey N Fedorov, Larisa K Shubina, Igor E Kasheverov, Heimo Ehmke, Thomas Steuber, Valentin A Stonik, Carsten Bokemeyer, Friedemann Honecker, Gunhild von Amsberg
Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of Rhizochalinin (Rhiz) - a novel sphingolipid-like marine compound - was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells...
September 10, 2016: Oncotarget
Andrew K Kwegyir-Afful, Robert D Bruno, Puranik Purushottamachar, Francis N Murigi, Vincent C O Njar
Metastatic castration-resistant prostate cancer (mCRPC) accounts for a high percentage of prostate cancer mortality. The proprietary compound galeterone (gal) was designed to inhibit proliferation of androgen/androgen receptor (AR)-dependent prostate cancer cell in vitro and in vivo and is currently in phase III clinical development. Additionally, clinical studies with gal revealed its superb efficacy in four different cohorts of patients with mCRPC, including those expressing splice variant AR-V7. Preclinical studies with gal show that it also exhibits strong antiproliferative activities against AR-negative prostate cancer cells and tumors through a mechanism involving phosphorylation of eIF2α, which forms an integral component of the eukaryotic mRNA translation complex...
September 12, 2016: FEBS Journal
Emmanuel S Antonarakis, Howard I Scher
No abstract text is available yet for this article.
August 31, 2016: European Urology
Martuza Sarwar, Julius Semenas, Regina Miftakhova, Athanasios Simoulis, Brian Robinson, Anette Gjörloff Wingren, Nigel P Mongan, David M Heery, Heather Johnsson, Per-Anders Abrahamsson, Nishtman Dizeyi, Jun Luo, Jenny L Persson
One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients...
August 31, 2016: Oncotarget
Karim Fizazi
The last 2 years (2014 and 2015) have witnessed major advances in the treatment of genitourinary malignancies. Of note and in marked contrast to previous years, all four major cancers (prostate cancer, testicular cancer, kidney cancer, and bladder cancer) have benefited from this progress. In prostate cancer, it was clearly demonstrated that a local treatment should be administered for high-risk localised disease. The standard of care was changed for patients with upfront metastatic disease with combined androgen deprivation therapy plus docetaxel becoming the new standard for fit patients with multiple bony metastases...
October 2016: European Journal of Cancer
Chan Ho Lee, Ja Yoon Ku, Jung Min Ha, Sun Sik Bae, Jeong Zoo Lee, Choung-Soo Kim, Hong Koo Ha
PURPOSE: This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. METHODS: We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC...
August 22, 2016: Prostate
Jingbo Qiao, Magdalena M Grabowska, Ingrid S Forestier-Roman, Janni Mirosevich, Thomas C Case, Dai H Chung, Justin M M Cates, Robert J Matusik, H Charles Manning, Renjie Jin
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone - gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells...
August 17, 2016: Oncotarget
Yafeng Ma, Alison Luk, Francis P Young, David Lynch, Wei Chua, Bavanthi Balakrishnar, Paul de Souza, Therese M Becker
Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set...
2016: International Journal of Molecular Sciences
Fangfang Qu, Wanling Xie, Mari Nakabayashi, Haitao Zhang, Seong Ho Jeong, Xiaodong Wang, Kazumasa Komura, Christopher J Sweeney, Oliver Sartor, Gwo-Shu Mary Lee, Philip W Kantoff
PURPOSE: We evaluated the association of prostate specific antigen (PSA) and androgen receptor splice variant-7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate (AA) and/or enzalutamide treatment in castration resistant prostate cancer (CRPC) patients. EXPERIMENTAL DESIGN: RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using Droplet Digital-PCR in retrospective cohorts treated with AA (N=81) or enzalutamide (N=51) for CRPC...
August 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Julia Hoefer, Mohammady Akbor, Florian Handle, Philipp Ofer, Martin Puhr, Walther Parson, Zoran Culig, Helmut Klocker, Isabel Heidegger
Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation...
July 29, 2016: Oncotarget
Diogo A Bastos, Emmanuel S Antonarakis
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide...
2016: Drug Design, Development and Therapy
Daisuke Nakata, Kazuhide Nakayama, Tsuneo Masaki, Akira Tanaka, Masami Kusaka, Tatsuya Watanabe
BACKGROUND: Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). METHODS: JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration...
December 2016: Prostate
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