Search results for: Androgen Receptor
#29035540 2017/10/16 Save this To Up
Targeted Clinical Nanoparticles for Precision Cancer Therapy based on Disease-specific Molecular Inflection Points.ional approaches based on clinical modular nanoplatforms are needed, in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit oncogenic signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early-stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical's polymeric coating, were tested, and resulted complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanoparmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatfom can be used in the clinic for patient stratification, as well as precision treatment based on the individual's unique disease features.
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#29033586 2017/10/16 Save this To Up
Targeting the androgen receptor in triple-negative breast cancer: current perspectives.Triple-negative breast cancer (TNBC) is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR) signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition.
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#29032717 2017/10/16 Save this To Up
BET inhibitors in metastatic prostate cancer: Therapeutic implications and rational drug combinations.The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas Covered: We speculate that a combination approach using BET inhibition with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BET inhibitors together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert Opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.
2957 related Products with: BET inhibitors in metastatic prostate cancer: Therapeutic implications and rational drug combinations.Prostate cancer, adjacent Breast cancer and matched Breast cancer and matched Breast cancer and matched Mid advanced stage kidney Lung cancer tissue array Prostate cancer tissue ar Prostate cancer tissue ar Prostate cancer and norma Prostate cancer tissue ar Multiple prostate cancer Prostate cancer tissue ar
#29032351 2017/10/16 Save this To Up
Testosterone-induced modulation of peroxisomal morphology and peroxisome-related gene expression in brown trout (Salmo trutta f. fario) primary hepatocytes.Disruption of androgenic signaling has been linked to possible cross-modulation with other hormone-mediated pathways. Therefore, our objective was to explore effects caused by testosterone - T (1, 10 and 50μM) in peroxisomal signaling of brown trout hepatocytes. To study the underlying paths involved, several co-exposure conditions were tested, with flutamide - F (anti-androgen) and ICI 182,780 - ICI (anti-estrogen). Molecular and morphological approaches were both evaluated. Peroxisome proliferator-activated receptor alpha (PPARα), catalase and urate oxidase were the selected targets for gene expression analysis. The vitellogenin A gene was also included as a biomarker of estrogenicity. Peroxisome relative volumes were estimated by immunofluorescence, and transmission electron microscopy was used for qualitative morphological control. The single exposures of T caused a significant down-regulation of urate oxidase (10 and 50μM) and a general up-regulation of vitellogenin. A significant reduction of peroxisome relative volumes and smaller peroxisome profiles were observed at 50μM. Co-administration of T and ICI reversed the morphological modifications and vitellogenin levels. The simultaneous exposure of T and F caused a significant and concentration-dependent diminishing in vitellogenin expression. Together, the findings suggest that in the tested model, T acted via both androgen and estrogen receptors to shape the peroxisomal related targets.
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#29031189 2017/10/14 Save this To Up
Renal Subcapsular xenografing of human fetal external genital tissue - A new model for investigating urethral development.In this paper, we introduce our novel renal subcapsular xenograft model for the study of human penile urethral and clitoral development. We grafted fifteen intact fetal penes and clitorides 8-11 weeks fetal age under the renal capsules of gonadectomized athymic mice. The mice were treated with a subcutaneous pellet of dihydrotestosterone (DHT), diethylstilbestrol (DES) or untreated with hormones. Xenografts were harvested after fourteen days of growth and analyzed via serial histologic sectioning and immunostaining for Ki-67, cytokeratins 6, 7 and 10, uroplakin and the androgen receptor. Non-grafted specimens of similar fetal age were sectioned and immunostained for the same antigenic markers. 14/15 (93.3%) grafts were successfully propagated and harvested. The developing urethral plate, urethral groove, tubular urethra, corporal bodies and preputial lamina were easily identifiable. These structures demonstrated robust cellularity, appropriate architecture and abundant Ki-67 expression. Expression patterns of cytokeratins 6, 7 and 10, uroplakin and the androgen receptor in xenografted specimens demonstrated characteristic male/female differences analogous to non-grafted specimens. DHT treatment reliably produced tubularization of nascent urethral and vestibular structures and male patterns of androgen receptor expression in grafts of both genetic sexes while estrogenic or hormonally absent conditions reliably resulted in a persistent open urethral/vestibular groove and female patterns of androgen receptor expression. This model's success enables further study into causal pathways by which endocrine-disrupting and endocrine-mimicking substances may directly cause disruption of normal human urethral development or hypospadias.
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#29030639 2017/10/14 Save this To Up
Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma.Clear cell renal cell carcinoma (ccRCC) is a gender-biased tumor. Here we report that there is also a gender difference between pulmonary metastasis and lymph node metastasis showing that the androgen receptor (AR)-positive ccRCC may prefer to metastasize to lung rather than to lymph nodes. A higher AR expression increases ccRCC hematogenous metastasis yet decreases ccRCC lymphatic metastases. Mechanism dissection indicates that AR enhances miR-185-5p expression via binding to the androgen response elements located on the promoter of miR-185-5p, which suppresses VEGF-C expression via binding to its 3' UTR. In contrast, AR-enhanced miR-185-5p also promotes HIF2α/VEGF-A expression via binding to the promoter region of HIF2α. Together, these results provide a unique mechanism by which AR can either increase or decrease ccRCC metastasis at different sites and may help us to develop combined therapies using anti-AR and anti-VEGF-C compounds to better suppress ccRCC progression.The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
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#29030409 2017/10/14 Save this To Up
Clinical relevance of androgen receptor alterations in prostate cancer.Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven. Molecular mechanisms behind epithelial AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intra-tumoural and adrenal androgen synthesis and promiscuous AR activation by other factors. This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs. The review will also discuss AR signalling in the tumour microenvironment and its possible relevance for metastatic growth and therapy.
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#29029032 2017/10/13 Save this To Up
FOXA1 expression is a strong independent predictor of early PSA recurrence in ERG negative prostate cancers treated by radical prostatectomy.FOXA1 is a transcription factor involved in androgen signaling with relevance for lineage specific gene expression of the prostate. The expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor expression, ERG status and other recurrent genomic alterations. FOXA1 expression was detectable in 97.6% of 8,227 interpretable cancers and considered strong in 28.5%, moderate in 46.2% and weak in 22.9% of cases. High FOXA1 expression was associated with TMPRSS2:ERG rearrangement and ERG expression (p<0.0001). High FOXA1 expression was linked to high Gleason grade, advanced pT stage and early PSA recurrence in ERG negative cancers (p<0.0001), while these associations were either weak or absent in ERG positive cancers. In ERG negative cancers, the prognostic role of FOXA1 expression was independent of Gleason grade, pT stage, pN stage, surgical margin status and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features such as biopsy Gleason grade, preoperative PSA, cT stage and FOXA1 expression (p<0.0001). Within ERG negative cancers, FOXA1 expression was also strongly associated with PTEN and 5q21 deletions (p<0.0001). High expression of FOXA1 is an independent prognostic parameter in ERG negative prostate cancer. Thus FOXA1 measurement might provide clinically useful information in prostate cancer.
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#29027610 2017/10/13 Save this To Up
Risk Factors for and Incidence of Seizures in Metastatic Castration-Resistant Prostate Cancer: A Real-World Retrospective Cohort Study.This real-world study assessed the prevalence, risk factors for, and incidence of seizures in patients with metastatic castration-resistant prostate cancer (mCRPC).
2254 related Products with: Risk Factors for and Incidence of Seizures in Metastatic Castration-Resistant Prostate Cancer: A Real-World Retrospective Cohort Study.Prostate cancer, adjacent Breast cancer and matched Breast cancer and matched Breast cancer and matched Mid advanced stage kidney Lung cancer tissue array Prostate cancer tissue ar Prostate cancer tissue ar Prostate cancer and norma Prostate cancer tissue ar Multiple prostate cancer Prostate cancer tissue ar
#29024781 2017/10/12 Save this To Up
The role of androgen receptors in atherosclerosis.Male disadvantage in cardiovascular health is well recognised. However, the influence of androgens on atherosclerosis, one of the major causes of many life-threatening cardiovascular events, is not well understood. With the dramatic increase in clinical prescription of testosterone in the past decade, concerns about the cardiovascular side-effects of androgen supplementation or androgen deprivation therapy are increasing. Potential atheroprotective effects of testosterone could be secondary to (aromatase-mediated) conversion into oestradiol or, alternatively, to direct activation of androgen receptors (AR). Recent development of animal models with cell-specific AR knockout has indicated a complex role for androgen action in atherosclerosis. Most studies suggest androgens are atheroprotective but the precise role of AR remains unclear. Increased use of AR knockout models should clarify the role of AR in atherogenesis and, thus, lead to exploitation of this pathway as a therapeutic target.
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