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https://www.readbyqxmd.com/read/29764864/targeting-the-hsp40-hsp70-chaperone-axis-as-a-novel-strategy-to-treat-castration-resistant-prostate-cancer
#1
Michael A Moses, Yeong Sang Kim, Genesis M Rivera-Marquez, Nobu Oshima, Matthew J Watson, Kristin Beebe, Catherine Wells, Sunmin Lee, Abbey D Zuehlke, Hao Shao, William E Bingman, Vineet Kumar, Sanjay Malhotra, Nancy L Weigel, Jason E Gestwicki, Jane Trepel, Leonard M Neckers
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with heat shock protein 40 (Hsp40)...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29756415/the-expression-of-androgen-receptor-and-its-variants-in-human-prostate-cancer-tissue-according-to-disease-status-and-its-prognostic-significance
#2
Sung Woo Park, Jung Hee Kim, Hyun Jung Lee, Dong Hoon Shin, Sang Don Lee, Sik Yoon
PURPOSE: To evaluate changes in the expression of androgen receptor (AR) and its variants (ARVs) in human prostate cancer (PCa) tissues according to disease status, and its prognostic significance following radical prostatectomy (RP). MATERIALS AND METHODS: A total of 282 PCa cases were evaluated, which included 252 localized PCa, 8 metastatic castration resistant prostate cancer (CRPC), and 22 benign prostatic hyperplasia (BPH) cases. Samples were collected from patients who underwent RP or transurethral resection and were stored in ethically approved tissue banks...
April 16, 2018: World Journal of Men's Health
https://www.readbyqxmd.com/read/29725990/gene-expression-analysis-of-immunomagnetically-enriched-circulating-tumor-cell-fraction-in-castration-resistant-prostate-cancer
#3
Markéta Škereňová, Veronika Mikulová, Otakar Čapoun, David Švec, Katarína Kološtová, Viktor Soukup, Hana Honová, Tomáš Hanuš, Tomáš Zima
BACKGROUND: Molecular characterization of tumors could be a key to therapeutic decision-making with regards to targeted therapies in castration-resistant prostate cancer (CRPC). A convenient solution may be non-invasive liquid biopsy testing of circulating tumor cells (CTCs). For this reason, CTC-enriched samples obtained by immunomagnetic separation (AdnaTest® ) were studied as a source material for high-throughput gene expression analysis using BioMark™. PATIENTS AND METHODS: CTC-enriched samples from 41 CRPC patients previously determined to be CTC positive using the AdnaTest® were retrospectively re-analysed for androgen receptor (AR) messenger RNA (mRNA), using the updated AdnaTest® ...
May 3, 2018: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/29682426/replication-study-androgen-receptor-splice-variants-determine-taxane-sensitivity-in-prostate-cancer
#4
Xiaochuan Shan, Gwenn Danet-Desnoyers, Fraser Aird, Irawati Kandela, Rachel Tsui, Nicole Perfito, Elizabeth Iorns
In 2015, as part of the Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative, we published a Registered Report (Shan et al., 2015) that described how we intended to replicate selected experiments from the paper "Androgen Receptor Splice Variants Determine Taxane Sensitivity in Prostate Cancer" (Thadani-Mulero et al., 2014). Here we report the results of those experiments. Growth of tumor xenografts from two prostate cancer xenograft lines, LuCaP 86.2, which expresses wild-type androgen receptor (AR) and AR variant 567, and LuCaP 23...
2018: PeerJ
https://www.readbyqxmd.com/read/29500328/digital-circulating-tumor-cell-analyses-for-prostate-cancer-precision-oncology
#5
Ellen Heitzer, Michael R Speicher
<b/> In this issue of Cancer Discovery , Miyamoto and colleagues adapted their microfluidic CTC-iChip isolation platform with a digital RNA-PCR readout for eight prostate-specific transcripts and two assays for the androgen receptor mRNA splice variant ARV7 and the TMPRSS2-ERG translocation transcript. In patients with metastatic castrate-resistant prostate cancer at initiating abiraterone therapy in a first-line setting, the resulting RNA-based digital circulating tumor cell signatures identified patients with a shorter overall survival, and in patients with clinically localized disease, the signatures identified those with seminal vesicle invasion and pelvic lymph node involvement...
March 2018: Cancer Discovery
https://www.readbyqxmd.com/read/28903374/resveratrol-enhances-polyubiquitination-mediated-arv7-degradation-in-prostate-cancer-cells
#6
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/28589901/resveratrol-enhances-polyubiquitination-mediated-arv7-degradation-in-prostate-cancer-cells
#7
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...
May 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28444169/androgen-receptor-regulation-of-local-growth-hormone-in-prostate-cancer-cells
#8
M Victoria Recouvreux, J Boyang Wu, Allen C Gao, Svetlana Zonis, Vera Chesnokova, Neil Bhowmick, Leland W Chung, Shlomo Melmed
Prostate cancer (PCa) growth is mainly driven by androgen receptor (AR), and tumors that initially respond to androgen deprivation therapy (ADT) or AR inhibition usually relapse into a more aggressive, castration-resistant PCa (CRPC) stage. Circulating growth hormone (GH) has a permissive role in PCa development in animal models and in human PCa xenograft growth. As GH and GH receptor (GHR) are both expressed in PCa cells, we assessed whether prostatic GH production is linked to AR activity and whether GH contributes to the castration-resistant phenotype...
July 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28373004/natural-killer-cells-suppress-enzalutamide-resistance-and-cell-invasion-in-the-castration-resistant-prostate-cancer-via-targeting-the-androgen-receptor-splicing-variant-7-arv7
#9
Shin-Jen Lin, Fu-Ju Chou, Lei Li, Chang-Yi Lin, Shuyuan Yeh, Chawnshang Chang
Despite the success of androgen-deprivation therapy (ADT) with the newly developed anti-androgen enzalutamide (Enz, also known as MDV3100) to suppress castration resistant prostate cancer (CRPC) in extending patient survival by an extra 4.8 months, eventually patients die with the development of Enz resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we identify an unrecognized role of Natural Killer (NK) cells in the prostate tumor microenvironment that can be better recruited to the CRPC cells to suppress ARv7 expression resulting in suppressing the Enz resistant CRPC cell growth and invasion...
July 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28235766/sigma1-targeting-to-suppress-aberrant-androgen-receptor-signaling-in-prostate-cancer
#10
Jeffrey D Thomas, Charles G Longen, Halley M Oyer, Nan Chen, Christina M Maher, Joseph M Salvino, Blase Kania, Kelsey N Anderson, William F Ostrander, Karen E Knudsen, Felix J Kim
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways...
May 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28224650/androgen-receptor-splice-variants-are-not-substrates-of-nonsense-mediated-decay
#11
Atinuke S Ajiboye, David Esopi, Srinivasan Yegnasubramanian, Samuel R Denmeade
BACKGROUND: Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated. There has been a suggestion that AR variants bearing premature termination codons and coding for truncated proteins should be regulated by the nonsense-mediated decay (NMD) mRNA surveillance pathway, suggesting that either the NMD pathway is dysfunctional in variant-expressing cell lines or that variants are somehow able to evade degradation by NMD...
June 2017: Prostate
https://www.readbyqxmd.com/read/28077788/androgen-receptor-splice-variants-and-prostate-cancer-from-bench-to-bedside
#12
REVIEW
Kristine M Wadosky, Shahriar Koochekpour
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/27886573/nuclear-transportation-of-exogenous-epidermal-growth-factor-receptor-and-androgen-receptor-via-extracellular-vesicles
#13
Jolene Read, Alistair Ingram, Hassan A Al Saleh, Khrystyna Platko, Kathleen Gabriel, Anil Kapoor, Jehonathan Pinthus, Fadwa Majeed, Talha Qureshi, Khalid Al-Nedawi
Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR...
January 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/27683182/a-phase-ii-trial-of-abiraterone-combined-with-dutasteride-for-men-with-metastatic-castration-resistant-prostate-cancer
#14
Rana R McKay, Lillian Werner, Elahe A Mostaghel, Rosina Lis, Olga Voznesensky, Zhenwei Zhang, Brett T Marck, Alvin M Matsumoto, Liran Domachevsky, Katherine A Zukotynski, Manoj Bhasin, Glenn J Bubley, Bruce Montgomery, Philip W Kantoff, Steven P Balk, Mary-Ellen Taplin
Purpose: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3...
February 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26944919/edelfosine-promotes-apoptosis-in-androgen-deprived-prostate-tumors-by-increasing-atf3-and-inhibiting-androgen-receptor-activity
#15
Thirupandiyur S Udayakumar, Radka Stoyanova, Mohammed M Shareef, Zhaomei Mu, Sakhi Philip, Kerry L Burnstein, Alan Pollack
Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line...
June 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26585210/addition-of-psma-adc-to-enzalutamide-therapy-significantly-improves-survival-in-in-vivo-model-of-castration-resistant-prostate-cancer
#16
Vincent A DiPippo, Holly M Nguyen, Lisha G Brown, William C Olson, Robert L Vessella, Eva Corey
BACKGROUND: Despite multiple new therapies available to patients with advanced castration-resistant prostate cancer (CRPC), the overall survival benefit still remains relatively short. Therefore, it is important to investigate additional treatment options that could achieve greater efficacy. Because of tumor heterogeneity and the development of resistance to treatment with single agents, combination therapies using existing drugs with new agents can potentially broaden individual therapeutic windows and achieve improved efficacy and safety profiles...
February 15, 2016: Prostate
https://www.readbyqxmd.com/read/26401448/registered-report-androgen-receptor-splice-variants-determine-taxane-sensitivity-in-prostate-cancer
#17
Xiaochuan Shan, Gwenn Danet-Desnoyers, Juan José Fung, Alan H Kosaka, Fraser Tan, Nicole Perfito, Joelle Lomax, Elizabeth Iorns
The Prostate Cancer Foundation-Movember Foundation Reproducibility Initiative seeks to address growing concerns about reproducibility in scientific research by conducting replications of recent papers in the field of prostate cancer. This Registered Report describes the proposed replication plan of key experiments from "Androgen Receptor Splice Variants Determine Taxane Sensitivity in Prostate Cancer" by Thadani-Mulero and colleagues (2014) published in Cancer Research in 2014. The experiment that will be replicated is reported in Fig...
2015: PeerJ
https://www.readbyqxmd.com/read/24882673/molecular-characterization-of-enzalutamide-treated-bone-metastatic-castration-resistant-prostate-cancer
#18
Eleni Efstathiou, Mark Titus, Sijin Wen, Anh Hoang, Maria Karlou, Robynne Ashe, Shi Ming Tu, Ana Aparicio, Patricia Troncoso, James Mohler, Christopher J Logothetis
BACKGROUND: Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations. DESIGN, SETTING, AND PARTICIPANTS: In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment...
January 2015: European Urology
https://www.readbyqxmd.com/read/24556717/androgen-receptor-splice-variants-determine-taxane-sensitivity-in-prostate-cancer
#19
Maria Thadani-Mulero, Luigi Portella, Shihua Sun, Matthew Sung, Alexandre Matov, Robert L Vessella, Eva Corey, David M Nanus, Stephen R Plymate, Paraskevi Giannakakou
Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active androgen receptor splice variants that drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC); however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for androgen receptor nuclear translocation and activity. In this study, we used a set of androgen receptor deletion mutants to identify the microtubule-binding domain of the androgen receptor, which encompasses the DNA binding domain plus hinge region...
April 15, 2014: Cancer Research
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