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Enzalutamide resistance

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https://www.readbyqxmd.com/read/28915573/lipid-catabolism-inhibition-sensitizes-prostate-cancer-cells-to-antiandrogen-blockade
#1
Thomas W Flaig, Maren Salzmann-Sullivan, Lih-Jen Su, Zhiyong Zhang, Molishree Joshi, Miguel A Gijón, Jihye Kim, John J Arcaroli, Adrie Van Bokhoven, M Scott Lucia, Francisco G La Rosa, Isabel R Schlaepfer
Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28903374/resveratrol-enhances-polyubiquitination-mediated-arv7-degradation-in-prostate-cancer-cells
#2
Sarah Wilson, Lucia Cavero, Dali Tong, Qiuli Liu, Kyla Geary, Nicholas Talamonti, Jing Xu, Junjiang Fu, Jun Jiang, Dianzheng Zhang
Although androgen deprivation therapy (ADT) serves as the primary treatment option for localized or metastatic prostate cancer, most cases eventually develop into castration-resistant prostate cancer (CRPC). However, androgen receptor (AR) continues to be functional in CRPC through various mechanisms, including the development of AR splicing variants, especially ARV7. Since it lacks the ligand binding domain but retains the intact DNA binding domain, ARV7 is constitutively active, which makes ARV7-positive prostate cancer responsive to neither abiraterone nor enzalutamide...
August 15, 2017: Oncotarget
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
#3
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)...
August 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28899970/targeting-prostate-cancer-subtype-1-by-forkhead-box-m1-pathway-inhibition
#4
Kirsi Ketola, Ravi Sn Munuganti, Alastair Davies, Ka Mun Nip, Jennifer L Bishop, Amina Zoubeidi
PURPOSE: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype with no treatment options available in the clinic. EXPERIMENTAL DESIGN: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28891793/regulation-of-the-glucocorticoid-receptor-via-a-bet-dependent-enhancer-drives-antiandrogen-resistance-in-prostate-cancer
#5
Neel Shah, Ping Wang, John Wongvipat, Wouter R Karthaus, Wassim Abida, Joshua Armenia, Shira Rockowitz, Yotam Drier, Bradley E Bernstein, Henry W Long, Matthew L Freedman, Vivek K Arora, Deyou Zheng, Charles L Sawyers
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28890248/innovative-therapies-to-overcome-resistance-to-enzalutamide-perspective-on-the-use-of-darolutamide
#6
EDITORIAL
Zoran Culig
No abstract text is available yet for this article.
September 7, 2017: European Urology
https://www.readbyqxmd.com/read/28881501/drug-drug-interaction-potential-in-men-treated-with-enzalutamide-mind-the-gap
#7
G E Benoist, I M van Oort, S Smeenk, A Javad, D M Somford, D M Burger, N Mehra, N P van Erp
AIM: Metastatic castration resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore more at risk for complications due to drug-drug interactions(DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide. METHODS: We conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting...
September 7, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28881288/hydroxytriazole-derivatives-as-potent-and-selective-aldo-keto-reductase-1c3-akr1c3-inhibitors-discovered-by-bioisosteric-scaffold-hopping-approach
#8
Agnese C Pippione, Alessandro Giraudo, Davide Bonanni, Irene M Carnovale, Elisabetta Marini, Clara Cena, Annalisa Costale, Daniele Zonari, Klaus Pors, Maria Sadiq, Donatella Boschi, Simonetta Oliaro-Bosso, Marco L Lolli
The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold...
August 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28874892/treatment-patterns-and-trends-in-patients-dying-of-prostate-cancer-in-quebec-a-population-based-study
#9
A Dragomir, J Rocha, M Vanhuyse, F L Cury, W Kassouf, J Hu, A G Aprikian
INTRODUCTION: Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. METHODS: The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases...
August 2017: Current Oncology
https://www.readbyqxmd.com/read/28866822/dutch-economic-value-of-radium-223-in-metastatic-castration-resistant-prostate-cancer
#10
Michel L Peters, Claudine de Meijer, Dirk Wyndaele, Walter Noordzij, Annemarie M Leliveld-Kors, Joan van den Bosch, Pieter H van den Berg, Agni Baka, Jennifer G Gaultney
BACKGROUND: The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated. METHODS: A cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons...
September 2, 2017: Applied Health Economics and Health Policy
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
#11
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
https://www.readbyqxmd.com/read/28865089/impact-of-enzalutamide-and-its-main-metabolite-n-desmethyl-enzalutamide-on-pharmacokinetically-important-drug-metabolizing-enzymes-and-drug-transporters
#12
Johanna Weiss, Jutta Kocher, Corina Mueller, Stephanie Rosenzweig, Dirk Theile
Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2, and ABCG2 mRNA...
September 1, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28855993/treatment-sequence-in-castration-resistant-prostate-cancer-a-retrospective-study-in-the-new-anti-androgen-era
#13
Senji Hoshi, Kenji Numahata, Kunio Ono, Nobuhiro Yasuno, Vladimir Bilim, Kiyotsugu Hoshi, Hiroshi Amemiya, Isoji Sasagawa, Shoichiro Ohta
In recent years, abiraterone acetate (AA) and enzalutamide (EZL) have become available for the treatment of cancer. Prior clinical trials have demonstrated the benefits of these agents in males with castration-resistant prostate cancer (CRPC). The optimal sequencing of available therapies in the context of efficacy and known cross-resistance remains uncertain. Based on the mechanisms of action and accessible clinical data, AA and EZL may be indicated for the early stages of prostate cancer. Until clinical trials are conducted to determine the best treatment sequence, individualized therapy is required for each patient based on the clinicopathological characteristics...
October 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28851578/moving-towards-precision-urologic-oncology-targeting-enzalutamide-resistant-prostate-cancer-and-mutated-forms-of-the-androgen-receptor-using-the-novel-inhibitor-darolutamide-odm-201
#14
Hendrik Borgmann, Nada Lallous, Deniz Ozistanbullu, Eliana Beraldi, Naman Paul, Kush Dalal, Ladan Fazli, Axel Haferkamp, Pascale Lejeune, Artem Cherkasov, Martin E Gleave
Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts...
August 26, 2017: European Urology
https://www.readbyqxmd.com/read/28844372/antitumour-activity-and-safety-of-enzalutamide-in-patients-with-metastatic-castration-resistant-prostate-cancer-previously-treated-with-abiraterone-acetate-plus-prednisone-for-%C3%A2-24-weeks-in-europe
#15
Johann S de Bono, Simon Chowdhury, Susan Feyerabend, Tony Elliott, Enrique Grande, Amal Melhem-Bertrandt, Benoit Baron, Mohammad Hirmand, Patrick Werbrouck, Karim Fizazi
BACKGROUND: Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. OBJECTIVE: To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment...
August 22, 2017: European Urology
https://www.readbyqxmd.com/read/28840192/androgen-receptor-as-a-mediator-and-biomarker-of-radioresistance-in-triple-negative-breast-cancer
#16
Corey Speers, Shuang G Zhao, Ben Chandler, Meilan Liu, Kari Wilder-Romans, Eric Olsen, Shyam Nyati, Cassandra Ritter, Prasanna G Alluri, Vishal Kothari, Daniel F Hayes, Theodore S Lawrence, Daniel E Spratt, Daniel R Wahl, Lori J Pierce, Felix Y Feng
Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines...
2017: NPJ Breast Cancer
https://www.readbyqxmd.com/read/28837141/metformin-reverses-prostate-cancer-resistance-to-enzalutamide-by-targeting-tgf-%C3%AE-1-stat3-axis-regulated-emt
#17
Qiuli Liu, Dali Tong, Gaolei Liu, Jing Xu, Khang Do, Kyla Geary, Dianzheng Zhang, Jun Zhang, Yao Zhang, Yaoming Li, Gang Bi, Weihua Lan, Jun Jiang
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28836508/circulating-tumor-cells-and-their-role-in-prostate-cancer
#18
REVIEW
Moritz Maas, Miriam Hegemann, Steffen Rausch, Jens Bedke, Arnulf Stenzl, Tilman Todenhöfer
Circulating tumor cells (CTC) have become an important biomarker in patients with advanced prostate cancer. CTC count has been demonstrated to be a prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In localized prostate cancer, a clear correlation between CTC counts and clinicopathological risk parameters and outcome has not been observed. Currently, the focus of research is shifting from CTC enumeration towards molecular characterization of CTC leading to the discovery of markers predicting treatment response...
August 22, 2017: Asian Journal of Andrology
https://www.readbyqxmd.com/read/28835168/structure-activity-relationship-analysis-of-carbobicyclo-and-oxabicyclo-succinimide-analogues-as-potential-androgen-receptor-antagonists
#19
Lingyan Wang, Jiazhong Li
Prostate cancer (PCa) is a frequently diagnosed male cancer and the second leading cause of cancer-related death in many countries. Due to various amino acid mutations occurred in the ligand binding domain of androgen receptor (AR), the patients were observed insensitive, even resistant to the marketed antiandrogens such as bicalutamide and enzalutamide, which emphasizes the urgent need for novel antiandrogens to solve drug resistance problem. Recently a series of carbobicyclo and oxabicyclo succinimide analogues were reported to effectively antagonize AR...
August 23, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28832175/-docetaxel-cabazitaxel-enzalutamide-versus-docetaxel-enzalutamide-in-patients-with-metastatic-castration-resistant-prostate-cancer
#20
I Richter, J Dvořák, J Bartoš
AIM: The aim of this retrospective study was to compare the efficacy of the sequence docetaxel-cabazitaxel-enzalutamide vs. docetaxel-enzalutamide in patients with metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: Of the cohort of 35 patients, 11 were treated with the sequence docetaxel-cabazitaxel-enzalutamide and 24 were treated with the sequence docetaxel-enzalutamide. The doses were as follows: docetaxel, 75 mg/m2; cabazitaxel, 25 mg/m2; and enzalutamide, 160 mg/day...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
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