Prospective association between alcohol intake and hormone-dependent cancer risk: modulation by dietary fiber intake.

PubMed

Chhim, Anne-Sophie; Fassier, Philippine; Latino-Martel, Paule; Druesne-Pecollo, Nathalie; Zelek, Laurent; Duverger, Lucie; Hercberg, Serge; Galan, Pilar; Deschasaux, Mélanie; Touvier, Mathilde

2015-07-01

Alcohol intake is associated with increased circulating concentrations of sex hormones, which in turn may increase hormone-dependent cancer risk. This association may be modulated by dietary fiber intake, which has been shown to decrease steroid hormone bioavailability (decreased blood concentration and increased sex hormone-binding globulin concentration). However, this potential modulation has not been investigated in any prospective cohort. Our objectives were to study the relation between alcohol intake and the risk of hormone-dependent cancers (breast, prostate, ovarian, endometrial, and testicular) and to investigate whether dietary fiber intake modulated these associations. This prospective observational analysis included 3771 women and 2771 men who participated in the Supplémentation en Vitamines et Minéraux Antioxydants study (1994-2007) and completed at least 6 valid 24-h dietary records during the first 2 y of follow-up. After a median follow-up of 12.1 y, 297 incident hormone-dependent cancer cases, including 158 breast and 123 prostate cancers, were diagnosed. Associations were tested via multivariate Cox proportional hazards models. Overall, alcohol intake was directly associated with the risk of hormone-dependent cancers (tertile 3 vs. tertile 1: HR: 1.36; 95% CI: 1.00, 1.84; P-trend = 0.02) and breast cancer (HR: 1.70; 95% CI: 1.11, 2.61; P-trend = 0.04) but not prostate cancer (P-trend = 0.3). In stratified analyses (by sex-specific median of dietary fiber intake), alcohol intake was directly associated with hormone-dependent cancer (tertile 3 vs. tertile 1: HR: 1.76; 95% CI: 1.10, 2.82; P-trend = 0.002), breast cancer (HR: 2.53; 95% CI: 1.30, 4.95; P-trend = 0.02), and prostate cancer (HR: 1.37; 95% CI: 0.65, 2.89; P-trend = 0.02) risk among individuals with low dietary fiber intake but not among their counterparts with higher dietary fiber intake (P-trend = 0.9, 0.8, and 0.6, respectively). The P-interaction between alcohol and dietary fiber

Breast and Prostate Cancer and Hormone-Related Gene Variant Study

Cancer.gov

The Breast and Prostate Cancer and Hormone-Related Gene Variant Study allows large-scale analyses of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism.

Combinatorial strategy of epigenetic and hormonal therapies: A novel promising approach for treating advanced prostate cancer.

PubMed

Motawi, Tarek K; Darwish, Hebatallah A; Diab, Iman; Helmy, Maged W; Noureldin, Mohamed H

2018-04-01

Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-β appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERβ expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERβ1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERβ1 agonist, in prostate cancer cell line PC-3. Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERβ1 expression, protein levels of active caspase-3, cyclin D1, β-catenin and VEGF. Treatment with these drugs exhibited an increase in ERβ1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and β-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis. The results support the notion that ERβ1 acts as a tumor suppressor protein and suggest that sequential ERβ1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer. Copyright © 2018. Published by Elsevier Inc.

Phase I Trial of Adenovirus-Mediated IL-12 Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following Therapy

DTIC Science & Technology

2005-10-01

salvage seed implant, cryotherapy ) or who have a rising PSA while on hormone therapy for locally advanced prostate cancer are as follows: a. A...Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following Therapy PRINCIPAL INVESTIGATOR: Simon J. Hall, MD...CONTRACT NUMBER Phase I Trial of Adenovirus-Mediated IL-12 Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following

Immunohistochemical expression of Hsp60 correlates with tumor progression and hormone resistance in prostate cancer.

PubMed

Castilla, Carolina; Congregado, Belén; Conde, José M; Medina, Rafael; Torrubia, Francisco J; Japón, Miguel A; Sáez, Carmen

2010-10-01

To investigate the expression of Hsp60 protein in prostate cancer biopsy samples, and its association with prognostic clinical parameters and hormone resistance and survival. Molecular chaperones are involved in protein folding, protein degradation, and protein trafficking among subcellular compartments. We selected 107 patients with localized and locally advanced prostate cancer at our hospital from 1999 through 2004. We performed an analysis by western blot and immunohistochemistry on paraffin-embedded tissue sections. Clinical data were used to determine associations between immunohistochemical expression of Hsp60 and tumor behavior. The expression level of Hsp60 was significantly increased in tumors with high Gleason score (P < .001). Hsp60 expression was also significantly associated with initial serum PSA levels (P < .01) and with the presence of lymph node metastasis (P < .003). In 50 locally advanced cancers treated by androgen ablation we found an association between high Hsp60-expressing tumors and an early onset of hormone refractory disease (P < .02) and reduced cancer-specific survival (P < .05). Hsp60 protein is overexpressed in poorly differentiated prostate cancers. Hsp60 expression is strongly associated with prognostic clinical parameters, such as Gleason score, initial serum PSA levels, and lymph node metastasis and with the onset of hormone-refractory disease and reduced cancer-specific survival. Identification of such markers could be of relevance in the clinical management of prostate cancer. Copyright © 2010 Elsevier Inc. All rights reserved.

Prognostic significance of obstructive uropathy in advanced prostate cancer.

PubMed

Oefelein, Michael G

2004-06-01

To report the incidence and prognostic implications of obstructive uropathy (OU) in patients with advanced prostate cancer receiving androgen deprivation therapy and to define the impact initial local therapy has on the development of OU in patients with prostate cancer who develop recurrence and begin androgen deprivation therapy. From a population of 260 patients with advanced prostate cancer diagnosed between 1986 and 2003, OU was identified in 51 patients. The OU treatment options included ureteral stent, percutaneous nephrostomy, transurethral resection of the prostate, Foley catheter placement, and urinary diversion. Overall survival and the factors that influenced survival were calculated using standard statistical methods. OU was diagnosed in 15 (16%) of 80 patients who received local therapy with curative intent and in whom local therapy subsequently failed and in 36 (19%) of 180 patients who had never received local therapy (P = 0.7, chi-square test). Of these 51 patients, 39 had bladder neck obstruction and 16 had ureteral obstruction. Overall survival was significantly worse for the men with OU compared with those without OU (41 versus 54 months). OU was associated with tumor stage and androgen-insensitive prostate cancer. OU results in significantly reduced survival in men with prostate cancer. In a select group of patients with prostate cancer with progression after local therapy (primarily radiotherapy), no statistically significant reduction in the development of OU was observed relative to patients matched for stage, grade, and pretreatment prostate-specific antigen level treated with androgen deprivation therapy alone. Aggressive advanced stage and hormone-insensitive disease are variables associated with OU.

The prognostic significance of prostate specific antigen in metastatic hormone-resistant prostate cancer.

PubMed Central

Fosså, S. D.; Waehre, H.; Paus, E.

1992-01-01

Twenty-seven of 152 patients (18%) with progressing hormone resistant prostate cancer had normal serum levels of prostate specific antigen (PSA less than or equal to 10 micrograms l-1), when referred for secondary treatment. PSA was significantly correlated with the extent of skeletal metastases (R: 0.35) and the levels of hemoglobin (R: -0.19) and serum alkaline phosphatase (R: 0.30). In a multivariate Cox regression analysis the survival of the 152 patients was not correlated with the PSA level but with the patients performance status, the level of hemoglobin, and the time between primary hormone treatment and relapse. The lack of serum PSA to predict survival may be explained by a heterogenous composition of hormone resistant prostate cancer as regards differentiated and/or PSA producing vs undifferentiated and/or PSA non-producing cells. PMID:1379059

A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate.

PubMed

Amato, Robert J; Teh, Bin S; Henary, Haby; Khan, Muhammad; Saxena, Somyata

2009-01-01

Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results. Chemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m(2) and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m(2) and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy. Data for 31 men (median age, 63 years [range, 41-74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%-99.9%) from a baseline value of 14.3 ng/ml (range, 1.9-497.9 ng/mL). Median time to progression was 34+ months (range, 14-68+ months). Median OS was 56+ months (range, 17-73+ months). Combination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial.

Recent advances in prostate development and links to prostatic diseases

PubMed Central

Powers, Ginny L.

2013-01-01

The prostate is a branched ductal-acinar gland that is part of the male reproductive tract. Prostate development depends upon the integration of steroid hormone signals, paracrine interactions between the stromal and epithelial tissue layers, and the actions of cell autonomous factors. Several genes and signalling pathways are known to be required for one or more steps of prostate development including epithelial budding, duct elongation, branching morphogenesis, and/or cellular differentiation. Recent progress in the field of prostate development has included the application of genome-wide technologies including serial analysis of gene expression (SAGE), expression profiling microarrays, and other large scale approaches to identify new genes and pathways that are essential for prostate development. The aggregation of experimental results into online databases by organized multi-lab projects including the Genitourinary Developmental Molecular Atlas Project (GUDMAP) has also accelerated the understanding of molecular pathways that function during prostate development and identified links between prostate anatomy and molecular signaling. Rapid progress has also recently been made in understanding the nature and role of candidate stem cells in the developing and adult prostate. This has included the identification of putative prostate stem cell markers, lineage tracing, and organ reconstitution studies. However, several issues regarding their origin, precise nature, and possible role(s) in disease remain unresolved. Nevertheless, several links between prostatic developmental mechanisms and the pathogenesis of prostatic diseases including benign prostatic hyperplasia and prostate cancer have led to recent progress on targeting developmental pathways as therapeutic strategies for these diseases. PMID:23335485

Response to luteinizing releasing hormone, thyrotrophic releasing hormone, and human chorionic gonadotropin administration in healthy men at different risks for prostatic cancer and in prostatic cancer patients.

PubMed

Hill, P; Wynder, E L; Garbaczewski, L; Garnes, H; Walker, A R

1982-05-01

A comparative study of the pituitary and testicular response to luteinizing releasing hormone (LHRH), thyrotrophic releasing hormone (TRH), and human chorionic gonadotrophin (HCG) administration was carried out in (a) low-risk young South African black men and high-risk North American black men for prostatic cancer and (b) healthy elderly South African men and South African black men with prostatic cancer. A comparable HCG response occurred in young South African and North American black men, while a greater release of prolactin, but a lesser release of luteinizing hormone in response to LHRH:TRH occurred in South African black men. The response to HCG was comparable in elderly and young South African black men, although the prolactin release in response to TRH was greater in elderly men. A more prolonged release of luteinizing hormone was evident in men with prostatic cancer. Higher estradiol and estrone but lower androstenedione levels occurred in men with prostatic cancer. Data suggest that, in the elderly South African black men with prostatic cancer, estrogen metabolism is modified and that either the estrogen level or the higher estrogen:androgen levels modify the pituitary response to LHRH:TRH. A Western diet enhanced the changes in hormone profiles evident in black South African men with prostatic cancer.

COMPARISON OF THE EFFECTS OF TWO AR ANTAGONISTS ON ANDROGEN DEPENDENT TISSUES WEIGHTS AND HORMONE LEVELS IN MALE RATS AND ON EXPRESSION OF THREE ANDROGEN DEPENDENT GENES IN THE VENTRAL PROSTATE

EPA Science Inventory

Comparison of the effects of two AR antagonists on tissue weights and hormone levels in male rats and on expression of three androgen dependent genes in the ventral prostate
VS Wilson, CR Wood, GA Held, CS Lambright, JS Ostby, JR Furr, LE Gray Jr. US EPA, ORD, NHEERL, RTD, ...

Abiraterone for Hormone-Sensitive Prostate Cancers

Cancer.gov

An NCI Cancer Currents blog post on results from two clinical trials that showed adding abiraterone to androgen-deprivation therapy improved survival for men with metastatic hormone-sensitive prostate cancer.

Recent Advances in Prostate Cancer Treatment and Drug Discovery.

PubMed

Nevedomskaya, Ekaterina; Baumgart, Simon J; Haendler, Bernard

2018-05-04

Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.

Gonadotropin-releasing hormone antagonist in the management of prostate cancer.

PubMed

Debruyne, Frans M J

2004-01-01

Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer. When treatment is started, LHRH agonists initially stimulate the release of LH, causing a surge in serum testosterone that can precipitate a "flare" phenomenon or worsening of disease, particularly in patients with bone metastatic disease. Gonadotropin-releasing hormone (GnRH) receptor antagonism represents a newer approach to medical castration. Abarelix is a pure GnRH receptor antagonist that is devoid of any LHRH agonist activity. Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge, as compared with LHRH agonists with or without a nonsteroidal antagonist. The safety profile in terms of adverse events is comparable between the 2 types of treatment, but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare.

Regulation of prostate cancer by hormone-responsive G protein-coupled receptors.

PubMed

Wang, Wei; Chen, Zhao-Xia; Guo, Dong-Yu; Tao, Ya-Xiong

2018-06-15

Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor. We highlight here GPCR regulation of prostate cancer by these GPCRs. Further therapeutic approaches targeting these GPCRs for the treatment of prostate cancer are summarized. Copyright © 2018. Published by Elsevier Inc.

Development of 17β-hydroxysteroid dehydrogenase type 3 as a target in hormone-dependent prostate cancer therapy.

PubMed

Ning, Xiaohui; Yang, Yan; Deng, Hong; Zhang, Qihao; Huang, Yadong; Su, Zhijian; Fu, Yongmei; Xiang, Qi; Zhang, Shu

2017-05-01

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed almost exclusively in the testes and specifically converts the weak androgenic androstenedione to active testosterone (T) in the presence of NADPH. Additionally, studies have demonstrated that 17β-HSD3 is over-expressed in hormone-dependent prostate cancer. T, which interacts with the androgen receptor (AR), eventually stimulates the growth of prostate cancer cells. Defects in T synthesis or action impair the development of the male phenotype during embryogenesis and cause the autosomal recessive disorder male pseudohermaphroditism. Affected individuals are often born with female-appearing external genitalia and are reared as females. Since 17β-HSD3 plays a central role in T production, it has been recognized as a promising therapeutic target to reduce the circulating level of androgens and to suppress androgen-sensitive tumor proliferation. In recent decades, improvements have been made in the development of 17β-HSD3 inhibitors. Herein, we give an overview of the main structure and function of human 17β-HSD3 and summarize steroidal and non-steroidal inhibitors of 17β-HSD3, which can be a potential target for prostate cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content.

PubMed

Shibata, Yasuhiro; Arai, Seiji; Miyazawa, Yoshiyuki; Shuto, Takahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Ito, Kazuto; Suzuki, Kazuhiro

2017-05-01

The effects of a steroidal antiandrogen (AA) and 5-alpha-reductase inhibitor (5ARI) on prostate tissue hormone content and metabolism are not fully elucidated. The objective of this study is to investigate the hormone content and metabolism of the prostate tissues of patients treated with AA or 5ARI using the ultra-sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Thirty-nine patients with benign prostatic hyperplasia (BPH) undergoing transurethral surgery were included. Serum and prostate tissue hormone and prostate tissue hormone metabolism analyses were performed using LC-MS/MS after 1 month of treatment with chlormadinone acetate (CMA; steroidal AA, 50 mg/day) or dutasteride (DUTA; dual 5ARI, 0.5 mg/day). Serum testosterone (T), dihydrotestosterone (DHT), and adrenal androgen levels were lower in the CMA group than the control group. Prostate tissue T and DHT levels were also lower in the CMA group than the control group. In the DUTA group, only serum and prostate DHT concentrations were reduced compared to the control group; in contrast, those of other hormones, especially T and 4-androstene-3,17-dione in the prostate tissue, showed marked elevations up to 70.4- and 11.4-fold normal levels, respectively. Moreover, the hormone metabolism assay confirmed that the conversion of T to DHT was significantly suppressed while that of T to 4-androstene-3,17-dione was significantly accelerated in the prostate tissue of DUTA-treated patients. Although treatment with AA and 5ARI show similar clinical outcomes, their effect on tissue hormone content and metabolism varied greatly. Prostate 77: 672-680, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

[Direct and indirect costs of luteinising hormone-releasing hormone analogues in the treatment of locally advanced or metastatic prostate cancer in Italy].

PubMed

Fadda, Valeria; Maratea, Dario

2015-12-01

When analyzing the use of luteinizing hormone-releasing hormone (LHRH) analogues for different clinical indications, current available evidence does not support a presumed drug class effect among the various LHRH in the treatment of prostate cancer. The following search key words were entered in the PubMed database and the NICE and FDA websites: “LHRH agonist AND prostatic cancer”, “androgen deprivation therapy”, “androgen suppression”, “buserelin”, “leuprorelin”, “goserelin”,“triptorelin”, “degarelix”. The direct costs included the following items: follow-up visits, diagnostic exams (e.g. prostate-specific antigen PSA) and drug costs. The indirect costs included working days lost by the patient. With intermittent therapy as a reference, leuprorelin injectable solution of 22,25 mg was associated with the lowest cost and degarelix with the highest cost. However, given the mandatory presence of a nurse for drug injection, the buserelin depot formulation was associated with the lowest cost. If the costs for hospital visits were added to drug costs, differences between the various therapeutic strategies were less remarkable. Our study showed how various factors (e.g. route of administration, frequency of administration, presence of a nurse for drug reconstitution and injection) should be taken into account by decision makers in addition to the price of drugs.

Comparison of Single-Agent Androgen Suppression for Advanced Prostate Cancer

PubMed Central

Lepor, Herbert

2005-01-01

Gonadotropin-releasing hormone (GnRH) agonists are the agents of choice for achieving androgen suppression in men with advanced prostate cancer. The GnRH agonists that have been developed and marketed for prostate cancer are leuprolide, goserelin, triptorelin, and histrelin. So far, there have been few randomized studies directly comparing these single-agent therapies; however, the literature and the data on file with the Food and Drug Administration suggest that triptorelin may be more reliable than leuprolide in maintaining castration levels of serum testosterone. The clinical significance of this benefit remains to be proven. PMID:16985882

Degarelix: a novel gonadotropin-releasing hormone blocker for the treatment of prostate cancer.

PubMed

Anderson, John

2009-05-01

Androgen deprivation therapy with gonadotropin releasing-hormone (GnRH) receptor agonists provides the mainstay of endocrine treatment for advanced prostate cancer. Although effective, GnRH agonists induce an initial testosterone surge, which can cause painful and potentially dangerous clinical flare. Degarelix is a novel GnRH receptor blocker that provides immediate, profound and sustained testosterone reduction, without an initial surge. In a Phase III trial, degarelix and leuprolide showed similar long-term efficacy in maintaining testosterone levels of 0.5 ng/ml or less over 1 year, and induced significantly faster testosterone and prostate-specific antigen suppression. Degarelix was well tolerated; the most common side effects were mild/moderate injection-site reactions and hot flashes. Findings to date suggest that degarelix may make an important contribution to the treatment of prostate cancer.

[Medical treatment of prostate cancer].

PubMed

Lobel, B; Cipolla, B; Labrador, J

1994-03-01

Hormone dependence of prostate cancer is well known. In 80% of cases with metastases, hormone suppression leads to the reduction of tumour volume and related disorders. However the treatment is generally palliative because malignant process recurs after about around 16 months. Mean survival is less than 3 years in these forms. Lack of response come always together with a poor prognosis, and there is 90% mortality at 2 years. Advanced prostatic cancer should not be treated with hormones if the patient has few symptoms and his quality of life is satisfactory. Symptomatic forms require hormone manipulation. Orchidectomy or LH-RH are recommended. Total androgen ablation (combined treatment) leads rapidly to more relief of symptoms, but its drawbacks and especially high cost indicate that its use should be weighed individually. Estramustine is not a first-lune treatment. Presently, there is no criteria to predict response to treatment.

Maspin Enhances the Anticancer Activity of Curcumin in Hormone-refractory Prostate Cancer Cells.

PubMed

Cheng, Wan-Li; Huang, Chien-Yu; Tai, Cheng-Jeng; Chang, Yu-Jia; Hung, Chin-Sheng

2018-02-01

Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated. The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis. Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells. Maspin can enhance the sensitivity of HRPC cells to curcumin treatment. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer.

PubMed

Nonomura, Norio; Takayama, Hitoshi; Nakayama, Masashi; Nakai, Yasutomo; Kawashima, Atsunari; Mukai, Masatoshi; Nagahara, Akira; Aozasa, Katsuyuki; Tsujimura, Akira

2011-06-01

• To evaluate tumour-associated macrophage (TAM) infiltration in prostate biopsy specimens as a possible prognostic factor for prostate cancer (PCa) after hormonal therapy. • Immunostaining of TAMs in prostate biopsy specimens was performed using a monoclonal antibody CD68 for 71 patients having PCa treated with hormonal therapy. • Six microscopic (×400) fields around the cancer foci were selected for TAM counting. • The median value of serum prostate-specific antigen (PSA) was 50.1 ng/mL, and the median TAM count was 22. • Recurrence-free survival was significantly better in patients with fewer TAMs (<22) than in those with higher numbers of TAMs (≥22) (P < 0.001). • TAM count was higher in those with higher serum PSA (PSA), higher Gleason score, clinical T stage or those with PSA failure. Cox multivariate analysis showed that TAM count is one of the prognostic factors for PCa treated by hormonal therapy (P < 0.0001). • TAM infiltration in prostate needle biopsy specimens is a useful predictive factor for PSA failure or progression of PCa after hormonal therapy. © 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.

Renal Capsule Xenografting and Subcutaneous Pellet Implantation for the Evaluation of Prostate Carcinogenesis and Benign Prostatic Hyperplasia

PubMed Central

Nicholson, Tristan M.; Uchtmann, Kristen S.; Valdez, Conrad D.; Theberge, Ashleigh B.; Miralem, Tihomir; Ricke, William A.

2013-01-01

New therapies for two common prostate diseases, prostate cancer (PrCa) and benign prostatic hyperplasia (BPH), depend critically on experiments evaluating their hormonal regulation. Sex steroid hormones (notably androgens and estrogens) are important in PrCa and BPH; we probe their respective roles in inducing prostate growth and carcinogenesis in mice with experiments using compressed hormone pellets. Hormone and/or drug pellets are easily manufactured with a pellet press, and surgically implanted into the subcutaneous tissue of the male mouse host. We also describe a protocol for the evaluation of hormonal carcinogenesis by combining subcutaneous hormone pellet implantation with xenografting of prostate cell recombinants under the renal capsule of immunocompromised mice. Moreover, subcutaneous hormone pellet implantation, in combination with renal capsule xenografting of BPH tissue, is useful to better understand hormonal regulation of benign prostate growth, and to test new therapies targeting sex steroid hormone pathways. PMID:24022657

Sex steroid hormone metabolism in relation to risk of aggressive prostate cancer

PubMed Central

Black, Amanda; Pinsky, Paul F.; Grubb, Robert L.; Falk, Roni T.; Hsing, Ann W.; Chu, Lisa; Meyer, Tamra; Veenstra, Timothy D.; Xu, Xia; Yu, Kai; Ziegler, Regina G.; Brinton, Louise A.; Hoover, Robert N.; Cook, Michael B.

2014-01-01

Background The combined action of androgens and estrogens—specifically their balance—may play a role in prostate carcinogenesis but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer. Methods In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort we measured serum estrone, estradiol and 13 estrogen metabolites, in the 2-, 4, or 16-hydroxylation pathways, using a liquid chromatography-tandem mass spectrometry assay. Cases (n=195) were non-Hispanic white men aged 55–70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n=195) were non-Hispanic white men without prostate cancer who were frequency-matched to cases by age and year at blood draw, time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Results Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st =0.27, 95% CI 0.12–0.59, p trend=0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st =2.44, 95% CI 1.34–4.45, p trend=0.001). Estradiol, estrone and estrogen metabolites were unrelated to risk. Conclusions Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer. Impact Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions. PMID:25178985

New Paradigms for Advanced Prostate Cancer

PubMed Central

Petrylak, Daniel P

2007-01-01

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy. PMID:17554403

Rooster feathering, androgenic alopecia, and hormone dependent tumor growth: What is in common?

PubMed Central

Mayer, Julie Ann; Chuong, Cheng-Ming; Widelitz, Randall

2015-01-01

Different epithelial organs form as a result of epithelial - mesenchymal interactions and share a common theme modulated by variations (Chuong edit. In Molecular Basis of Epithelial Appendage Morphogenesis, 1998). One of the major modulators is the sex hormone pathway that acts on the prototype signaling pathway to alter organ phenotypes. Here we focus on how the sex hormone pathway interfaces with epithelia morphogenesis related signaling pathways. We first survey these sex hormone regulated morphogenetic processes in various epithelial organs. Sexual dimorphism of hairs and feathers has implications in sexual selection. Diseases of these pathways result in androgenic alopecia, hirsutism, henny feathering, etc. The growth and development of mammary glands, prostate glands and external genitalia essential for reproductive function are also dependent on sex hormones. Diseases affecting these organs include congenital anomalies and hormone dependent type of breast and prostate cancers. To study the role of sex hormones in new growth in the context of system biology / pathology, an in vivo model in which organ formation starts from stem cells is essential. With recent developments (Yu et al., The morphogenesis of feathers. Nature 420:308–312, 2002), the growth of tail feathers in roosters and hens has become a testable model in which experimental manipulations are possible. We show exemplary data of differences in their growth rate, proliferative cell population and signaling molecule expression. Working hypotheses are proposed on how the sex hormone pathways may interact with growth pathways. It is now possible to test these hypotheses using the chicken model to learn fundamental mechanisms on how sex hormones affect organogenesis, epithelial organ cycling, and growth related tumorigenesis. PMID:15617560

Precision medicine for advanced prostate cancer.

PubMed

Mullane, Stephanie A; Van Allen, Eliezer M

2016-05-01

Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer. Although primary prostate cancers do not harbor highly recurrent targetable genomic alterations, recent reports on the genomics of metastatic castration-resistant prostate cancer has shown multiple targetable alterations in castration-resistant prostate cancer metastatic biopsies. Therapeutic implications include targeting prevalent DNA repair pathway alterations with PARP-1 inhibition in genomically defined subsets of patients, among other genomically stratified targets. In addition, multiple recent efforts have demonstrated the promise of liquid tumor profiling (e.g., profiling circulating tumor cells or cell-free tumor DNA) and highlighted the necessary steps to scale these approaches in prostate cancer. Although still in the initial phase of precision medicine for prostate cancer, there is extraordinary potential for clinical impact. Efforts to overcome current scientific and clinical barriers will enable widespread use of precision medicine approaches for advanced prostate cancer patients.

Emerging Therapies in Metastatic Prostate Cancer.

PubMed

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Precision medicine for advanced prostate cancer

PubMed Central

Mullane, Stephanie A.; Van Allen, Eliezer M.

2016-01-01

Purpose of review Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer. Recent findings Although primary prostate cancers do not harbor highly recurrent targetable genomic alterations, recent reports on the genomics of metastatic castration-resistant prostate cancer has shown multiple targetable alterations in castration-resistant prostate cancer metastatic biopsies. Therapeutic implications include targeting prevalent DNA repair pathway alterations with PARP-1 inhibition in genomically defined subsets of patients, among other genomically stratified targets. In addition, multiple recent efforts have demonstrated the promise of liquid tumor profiling (e.g., profiling circulating tumor cells or cell-free tumor DNA) and highlighted the necessary steps to scale these approaches in prostate cancer. Summary Although still in the initial phase of precision medicine for prostate cancer, there is extraordinary potential for clinical impact. Efforts to overcome current scientific and clinical barriers will enable widespread use of precision medicine approaches for advanced prostate cancer patients. PMID:26909474

Increased survival in men with metastatic prostate cancer receiving chemo and hormone therapy

Cancer.gov

Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a NIH-supporte

A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

PubMed

Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

2014-10-01

Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

PubMed Central

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer.

PubMed

Heyns, C F; Simonin, M-P; Grosgurin, P; Schall, R; Porchet, H C

2003-08-01

To compare the efficacy of monthly administrations of the luteinizing hormone-releasing hormone agonists triptorelin pamoate and leuprolide acetate to induce and maintain castrate levels of serum testosterone in men with advanced prostate cancer. Men with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or leuprolide 7.5 mg. The agent was injected intramuscularly every 28 days for nine injections. Primary endpoints were the percentages of men whose serum testosterone concentrations declined to and were maintained at or below castrate levels (hormone levels, bone pain, prostate specific antigen levels, quality of life, testosterone pharmacodynamics, survival, and safety variables. In all, 284 men received either triptorelin (140) or leuprolide (144). The percentage of men with castrate levels of serum testosterone was lower at 29 days for triptorelin than for leuprolide (91.2% vs 99.3%; point estimate - 8.0, 95% confidence interval - 16.9% to - 1.4%), but equivalent at 57 days (97.7% vs 97.1%). The mean (98.8% vs 97.3%) and cumulative (96.2% vs 91.2%) castration maintenance rates between 29 and 253 days were equivalent between the treatment groups. Secondary endpoints were equivalent between treatment groups except for the 9-month survival rate, which was significantly higher for triptorelin than for leuprolide (97.0% vs 90.5%; P = 0.033). Both treatments were well tolerated. Triptorelin reduced testosterone concentrations less rapidly, but maintained castration as effectively as leuprolide. There was no evidence that the slower onset of castration caused deleterious effects.

Variations of serum testosterone levels in prostate cancer patients under LH-releasing hormone therapy: an open question.

PubMed

Reis, Leonardo Oliveira

2012-06-01

The hypothesis 'the lower the better when achieving castration levels of testosterone' is based on the data from second-line hormonal manipulation and its molecular basis, and on better oncological results reported for lower castration levels in prostate cancer (PCa) patients, including those achieved with maximal androgen blockade. In this regard, the equivalence of surgical and different pharmacological castrations has been controversial. The modified amino acid structure that makes LH-releasing hormone (LHRH) analogs more potent than LHRH, and the method of delivering the analogs impacts on bioavailibility and potentially causes differences in androgen levels and in its final oncological efficacy. In addition to this, there is a myriad of circumstances, such as those related to ethnic variations and co-morbidities, which uniquely impact on the pharmacological approach in a highly heterogeneous population of castration-resistant prostate cancer (CRPC) patients. Ineffective testosterone suppression through hormonal escape is currently poorly recognized and may result in increased PCa mortality. Until now, the optimal serum testosterone level in patients under castration, and the impact of its variations in patients under LHRH therapy, remain open questions and have been merged to a broad spectra of patients who are highly heterogeneous. This heterogeneity relates to a number of mechanisms regarding response to treatment, which influences the biology of the relapsing tumor and the sensitivity to subsequent therapies in the individual patient. The rationale to achieve testosterone levels below 20-50 ng/dl warrant further investigation as these levels have recently rescued CRPC patients. In the last few years and months, important advancements in prostate cancer treatment have been achieved. Nevertheless, these advances are measured in a few months of additional survival and under high costs, not available to most of the world population, compared with the benefits

[Neuroendocrine differentiation in prostate adenocarcinoma].

PubMed

Ramírez-Balderrama, Lázaro; López-Briones, Sergio; Daza-Benítez, Leonel; Macías, Maciste H; López-Gaytán, Teresa; Pérez-Vázquez, Victoriano

2013-01-01

The human prostate is a gland composed of many types of cells and extracellular components with specific functions. The stromal compartment includes nerve tissue, fibroblasts, lymphocytes, macrophages, endothelial cells, and smooth muscular cells. The epithelial compartment is composed of luminal epithelial cells, basal cells, and a lesser number of neuroendocrine cells, which are transcendental in growth regulation, differentiation, and secretory function. In prostate cancer, neuroendocrine cells replicate especially in high grade and advanced stage, and hormonally treated tumoral cells adopt characteristics that make them resistant to hormonal deprivation. Androgen receptors have a crucial role in tumorigenesis of prostate adenocarcinoma. Deprivation hormone therapy blocks the expression of androgen receptors in the prostatic epithelial cells. Neuroendocrine cells lack androgen receptors; their growth is hormonally independent and that is why deprivation hormonal therapy does not eliminate the neoplasic neuroendocrine cells. In contrast, these types of cells proliferate after therapy and make a paracrine network, stimulating the proliferation of androgen-independent neoplastic cells, which finally lead to tumoral recurrence. In this work we describe the neuroendocrine function in normal tissue and in prostatic adenocarcinoma, including neoplasic proliferation stimulation, invasion, apoptosis resistance, and angiogenesis, and describe some molecular pathways involved in this neuroendocrine differentiation.

Up regulation of the steroid hormone synthesis regulator HSD3B2 is linked to early PSA recurrence in prostate cancer.

PubMed

Neubauer, Emily; Latif, Morwari; Krause, Jenny; Heumann, Asmus; Armbrust, Moritz; Luehr, Clara; Fraune, Christoph; Hube-Magg, Claudia; Kluth, Martina; Möller-Koop, Christina; Sauter, Guido; Simon, Ronald; Beyer, Burkhard; Pompe, Raisa S; Thederan, Imke; Schlomm, Thorsten; Büscheck, Franziska

2018-05-24

HSD3B2 plays a crucial role in steroid hormone biosynthesis and is thus of particular interest in hormone dependent tumors such as prostate cancer. To clarify the clinical relevance of HSD3B2 expression in prostate cancer, we analyzed HSD3B2 protein expression by immunohistochemistry on our preexisting tissue microarray with 12.247 annotated cancers. Compared with normal tissue cytoplasmic HSD3B2 staining was stronger in prostate cancers. In 9371 interpretable cancers, HSD3B2 expression was found in 95.5% of cancers and was considered weak in 29.9%, moderate in 40.7% and strong in 24.9%. HSD3B2 up regulation was linked to advanced pathological tumor stage (pT), high Gleason grade, elevated preoperative PSA levels (p < 0.0001 each), lymph node metastasis (p = 0.0019), accelerated cell proliferation (p < 0.0001), androgen receptor (AR) expression (p < 0.0001), and early biochemical recurrence (p < 0.0001). HSD3B2 up regulation was only marginally more frequent in ERG positive (98%) than in ERG negative cancers (94%; p < 0.0001) and was strongly linked to deletions of 5q and 6q (p < 0.0001 each). Multivariate analyses showed that the prognostic impact of HSD3B2 expression was independent of established preoperative, but not of postoperative prognostic parameters. In summary, the results of our study demonstrate that HSD3B2 is strongly up regulated in a fraction of prostate cancers that are characterized by increased AR signaling, adverse tumor phenotype and early biochemical recurrence. Copyright © 2018 Elsevier Inc. All rights reserved.

Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer.

PubMed

Kitamura, T

2001-02-01

Estramustine phosphate sodium (EMP) was first introduced in the early 1970s for the treatment of prostate cancer, when EMP was supposed to have the dual effect of estrogenic activity and cytotoxicity. For the following decades, it was used mainly in hormone-refractory cases, with a conventional dosage of 4-9 capsules/day, which showed a 30-35% objective response rate. However, a very limited number of cases have been reported that used EMP as a first-line monotherapy in the conventional dosage. One study showed a response rate of 82%, which is at least as effective as conventional estrogen (diethylstilbestrol; DES) monotherapy. Nevertheless, EMP was almost abandoned for the treatment of prostate cancer because of severe adverse side-effects, especially in the cardiovascular system and gastrointestinal tract. Recently, two facts have become evident. First, EMP interferes with cellular microtubule dynamics but does not show alkylating effects. Second, EMP is able to produce a complex with calcium when dairy products are taken concomitantly with EMP, resulting in a decrease in the absorption rate of EMP from the gut. Many clinical trials have been undertaken without warning against concomitant dairy product intake since the introduction of EMP. This fact will jeopardize almost all the clinical trials performed before 1990. It is considered that response rates have been underestimated and better results could have been obtained because side-effects decrease dose-dependently. Low-dose EMP monotherapy (2 capsules/day) has been performed infrequently in previously untreated advanced prostate cancer. The only large trial by the European Organization for Research and Treatment of Cancer in 1984 was biased in selecting patients. Nevertheless, the response rate of EMP is comparable to that of DES. In this study, the adverse side-effects of EMP were less than that of DES. Recently, a study was conducted at the University of Tokyo of 11 patients with advanced prostate cancer on

Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r.

PubMed

Le, H Carl; Lupu, Mihaela; Kotedia, Khushali; Rosen, Neal; Solit, David; Koutcher, Jason A

2009-11-01

17-Allylamino, 17-demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells, has shown promising results against several cancers, including hormone-resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as androgen receptor and HER2/neu, were reduced 4 h post 17-allylamino, 17-demethoxygeldanamycin treatment. Posttreatment metabolic changes have also been observed in several tumor cell lines. In this study, total choline distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before and at 4 h and 48 h after a single-bolus 17-allylamino, 17-demethoxygeldanamycin treatment at 100 mg/kg, using proton MR spectroscopy. Our results show that tumor total choline levels declined 4 h after the treatment for CWR22 (P = 0.001) and 48 h post treatment for CWR22r (P = 0.003). Metabolic changes, in particular of total choline intensity detected by proton magnetic resonance spectroscopic imaging (MRSI), are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P = 0.01 at 14 days post treatment), and a constant prostate specific antigen level versus increasing prostate specific antigen for control CWR22 (P = 0.01). Metabolic changes in total choline by proton MRSI can be used as an early biomarker of response for advanced-stage prostate cancer in targeted therapy such as 17-allylamino, 17-demethoxygeldanamycin. (c) 2009 Wiley-Liss, Inc.

[Treatment for locally advanced prostate cancer: value of surgery].

PubMed

Azuma, Haruhito; Katsuoka, Yoji

2006-06-01

Surgical therapy is not only a therapeutic method but also an important procedure to provide useful information in determining a postoperative treatment strategy. Compared with postoperative cancer staging based on specimens obtained during surgery, more than 30% of cancers were inaccurately staged preoperatively, even when a current advanced diagnostic imaging technique was used. Compared with postoperative histological 30-40% of cancer staging were inaccurately staged based on a preoperative biopsy. These misstaging cases pose a significantly important problem. Approximately 15% and 30% of clinical stage C prostate cancers have been rated as pT2 and pN(+), respectively. Patients with pT3 prostate cancer who underwent radical prostatectomy had 5-year and 10-year overall survival rates of 82% and 67%, respectively, which were comparable to those in patients with pT2 prostate cancer (82% and 67%, respectively). However, patients with prostate cancer rated as pT4 and pN(+) had very poor outcomes with 5-year overall survival rates of 42.4% and 32.6%, respectively. Therefore, even in patients with stage C prostate cancer, surgical therapy should be recommended if no infiltration of adjacent tissue has been noted and the operation is applicable; and an optimal postoperative therapeutic strategy should be selected based on the accurate pathological staging and histological grading using postoperative pathological specimens. Such approaches will prevent unnecessary hormone therapy in patients with pT2 prostate cancer and prevent missing optimal timing for radical cure, as well as allowing appropriate therapy to be selected for patients with pT4 and pN(+) prostate cancer, for whom prognosis may be poor.

Addition of docetaxel and/or zoledronic acid to standard of care for hormone-naive prostate cancer: a cost-effectiveness analysis.

PubMed

Zhang, Pengfei; Wen, Feng; Fu, Ping; Yang, Yu; Li, Qiu

2017-07-31

The effectiveness of the addition of docetaxel and/or zoledronic acid to the standard of care (SOC) for hormone-naive prostate cancer has been evaluated in the STAMPEDE trial. The object of the present analysis was to evaluate the cost-effectiveness of these treatment options in the treatment of advanced hormone-naive prostate cancer in China. A cost-effectiveness analysis using a Markov model was carried out from the Chinese societal perspective. The efficacy data were obtained from the STAMPEDE trial and health utilities were derived from previous studies. Transition probabilities were calculated based on the survival in each group. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by 1-way sensitivity analysis and probabilistic sensitivity analysis. SOC alone generated an effectiveness of 2.65 quality-adjusted life years (QALYs) at a lifetime cost of $20,969.23. At a cost of $25,001.34, SOC plus zoledronic acid was associated with 2.69 QALYs, resulting in an ICER of $100,802.75/QALY compared with SOC alone. SOC plus docetaxel gained an effectiveness of 2.85 QALYs at a cost of $28,764.66, while the effectiveness and cost data in the SOC plus zoledronic acid/docetaxel group were 2.78 QALYs and $32,640.95. Based on the results of the analysis, SOC plus zoledronic acid, SOC plus docetaxel, and SOC plus zoledronic acid/docetaxel are unlikely to be cost-effective options in patients with advanced hormone-naive prostate cancer compared with SOC alone.

Molecular Determinants of Hormone Refractory Prostate Cancer

DTIC Science & Technology

2017-07-01

Award Number: W81XWH-12-1-0062 TITLE: Molecular Determinants of Hormone Refractory Prostate Cancer PRINCIPAL INVESTIGATOR: Atish Choudhury...ABOVE ADDRESS. 1. REPORT DATE July 2017 2. REPORT TYPE Annual 3. DATES COVERED 1 July 2012 - 30 June 2017 4. TITLE AND SUBTITLE Molecular ...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT We have performed a high throughput, in vivo genetic screen to identify kinases that permit androgen

Use of androgen deprivation therapy in prostate cancer: indications and prevalence

PubMed Central

Connolly, Roisin M; Carducci, Michael A; Antonarakis, Emmanuel S

2012-01-01

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease. Controversies remain, however, surrounding the optimal timing, duration and schedule of these hormonal approaches. Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer. This review highlights the various androgen-directed treatment options available to men with prostate cancer, their specific indications and the evidence supporting each approach, as well as patterns of use of hormonal therapies. PMID:22231299

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer.

PubMed

Lebret, Thiery; Rouanne, Mathieu; Hublarov, Oleg; Jinga, Viorel; Petkova, Lidiya; Kotsev, Rumen; Sinescu, Ioanel; Dutailly, Pascale

2015-06-01

Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2-99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6-99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0-95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer.

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer

PubMed Central

Rouanne, Mathieu; Hublarov, Oleg; Jinga, Viorel; Petkova, Lidiya; Kotsev, Rumen; Sinescu, Ioanel; Dutailly, Pascale

2015-01-01

Objectives: Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. Methods: In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Results: Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2–99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6–99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0–95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). Conclusions: This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer. PMID:26161143

Advanced Prostate Cancer

MedlinePlus

... to learn about these types of treatments. This article is for men with metastatic and castrate-resistant ... Related Resources Urology 101 Fact Sheet UrologyHealth extra® Articles What is Advanced Prostate Cancer? Keeping Your Bones ...

Liarozole (R75251) in hormone-resistant prostate cancer patients.

PubMed

Dijkman, G A; Fernandez del Moral, P; Bruynseels, J; de Porre, P; Denis, L; Debruyne, F M

1997-09-15

Liarozole is an imidazole derivative that has been identified as an inhibitor of the cytochrome P450-dependent all-trans retinoid acid (RA) breakdown. RA is one of the principal endogenous compounds that controls growth and differentiation of epithelial tissues in mammals. Fifty-five patients with hormone-resistant prostate cancer in progression, following at least first-line androgen ablation therapy, were evaluated. Thirty-one patients were treated with liarozole 300 mg b.i.d., while 24 patients started with 150 mg b.i.d., which was increased to 300 mg b.i.d. after 4 or 8 weeks. Two patients were not evaluable because they withdrew after initial consent. The WHO performance status was 0 (n = 18), 1 (n = 22), 2 (n = 17), and 3 (n = 6). Most patients (80%) used analgesics. For 11 out of the 53 patients, treatment lasted less than 1 month (they were therefore not evaluable for response) due to: poor compliance (n = 1); early death (n = 3); side-effects (n = 2); and decline of physical condition and continuous progression (n = 4). One patient refused to report for follow-up. In all responders, except one, the dose was increased to 300 mg b.i.d. In 23 of the 42 patients evaluable for response, the pain score improved. In 5 patients the pain score had reduced from 2 or 3 to 0. In 11 out of the 42 patients there was a 1-point improvement of WHO performance status. The prostatic-specific antigen (PSA) response rate was 41%; 15 out of 42 evaluable patients presented a decrease of > or = 50%, whereas PSA normalized in 2 further patients. Most of the side effects mimicked retinoid acid toxicity: cutaneous manifestations (such as dry skin, dry lips, sticky skin, brittle nails, erythema, or itch). All patients experienced one or more of these side effects. Other side effects include nausea, fatigue, and slight alopecia. Liarozole can be an enrichment of the therapeutic armamentarium for treatment of hormone-resistant prostate cancer patients after first-line androgen ablation

[Prostate cancer and new hormonal treatments: mechanism of action and main clinical results].

PubMed

Neuzillet, Y; Flamand, V; Lebdai, S; Villers, A; Lebret, T

2013-10-01

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Strategies to Circumvent Testosterone Surge and Disease Flare in Advanced Prostate Cancer: Emerging Treatment Paradigms.

PubMed

Pokuri, Venkata K; Nourkeyhani, Houman; Betsy, Bodie; Herbst, Laurie; Sikorski, Marcus; Spangenthal, Edward; Fabiano, Andrew; George, Saby

2015-07-01

The testosterone surge and disease flare is a feared complication from initiation of gonadotropin-releasing hormone (GnRH) agonist treatment in advanced prostate adenocarcinoma. It is a common practice to start an average 7-day pretreatment regimen with an antiandrogen agent before initiating GnRH agonist therapy, to circumvent disease flare from testosterone surge. However, this might not be the best strategy and can be harmful, especially in patients at high risk of imminent organ damage from minimal testosterone surge. Surgical castration is a simple and cost-effective method that should be considered in these scenarios. But most patients refuse this procedure because of the permanent and psychologic impact of surgery. Novel GnRH antagonists, such as degarelix, and cytochrome P450 17 (CYP17) enzyme inhibitors, such as ketoconazole, achieve castrate-equivalent serum testosterone levels much faster than traditional GnRH agonists without the need for coadministration of antiandrogens. This article reports on 3 cases of impending oncologic emergencies in advanced prostate adenocarcinoma treated promptly with degarelix and ketoconazole without any disease flare related to testosterone surge. In the setting of symptomatic hormone-naïve metastatic prostate cancer, the authors suggest clinical trials using abiraterone, orteronel, and other newer agents that target the CYP17 axis (eg, ketoconazole) for fine-tuning the emergent medical castration methods and avoiding the dangers from the flare phenomenon. Copyright © 2015 by the National Comprehensive Cancer Network.

Retrospective analysis of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide for hormone-refractory prostate cancer.

PubMed

Hatano, Koji; Nonomura, Norio; Nishimura, Kazuo; Kawashima, Atsunari; Mukai, Masatoshi; Nagahara, Akira; Nakai, Yasutomo; Nakayama, Masashi; Takayama, Hitoshi; Tsujimura, Akira; Okuyama, Akihiko

2011-02-01

To evaluate the clinical utility of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide as a treatment for patients with hormone-refractory prostate cancer. Fifty-seven patients with hormone-refractory prostate cancer were treated with an oral administration of dexamethasone (1.0 mg/day), uracil plus tegafur (400 mg/day) and cyclophosphamide (100 mg/day). The median patient age was 71 years. Sixteen patients had symptomatic bone metastasis, 31 had asymptomatic bone metastasis and 8 showed lymph node metastasis. Eight patients presented with only biochemical progression as evaluated by serum prostate-specific antigen levels. Thirty-six (63%) of 57 patients demonstrated a ≥50% decline in serum prostate-specific antigen levels. The median time to prostate-specific antigen progression was 7.2 months. In patients with a prostate-specific antigen decline of ≥50%, the median time to progression was 13.3 months. With respect to pre-treatment markers, the duration of response to initial hormonal treatment was associated with the time to prostate-specific antigen progression. In 11 of 16 (69%) patients who complained of bone pain, the pain improved and became stable in 5 of those patients (31%). Most adverse events were mild and only three (5%) patients showed neutropenia of Grade 3 or higher. The combination of dexamethasone, uracil plus tegafur and cyclophosphamide is an effective and well tolerated regimen for hormone-refractory prostate cancer. To evaluate the survival benefits, further randomized studies are required.

Do differences in age specific androgenic steroid hormone levels account for differing prostate cancer rates between Arabs and Caucasians?

PubMed

Kehinde, Elijah O; Akanji, Abayomi O; Al-Hunayan, Adel; Memon, Anjum; Luqmani, Yunus; Al-Awadi, Khaleel A; Varghese, Ramani; Bashir, Abdul Aziz; Daar, Abdallah S

2006-04-01

Factors responsible for the low incidence of clinical prostate cancer in the Arab population remain unclear, but may be related to differences in androgenic steroid hormone metabolism between Arabs and other populations, especially as prostate cancer is believed to be androgen dependent. We therefore measured the levels of serum androgenic steroids and their binding proteins in Arab men and compared results obtained with values reported for Caucasian populations to determine if any differences could at least partially account for differences in incidence of prostate cancer rates between the two populations. Venous blood samples were obtained from 327 unselected apparently healthy indigenous Arab men (Kuwaitis and Omanis) aged 15-79 years. Samples were also obtained from 30 Arab men with newly diagnosed prostate cancer. Serum levels of total testosterone (TT), sex hormone binding globulin (SHBG), derived free androgen index (FAI); adrenal C19 -steroids, dehydroepiandrosterone sulfate (DHEAS) and androstenedione (ADT) were determined by chemiluminescent immunoassay. Age specific reference intervals, mean and median for each analyte were determined. Frequency distribution pattern for each hormone was plotted. The reference range for hormones with normal distribution was mean +/- 2SD and 2.5-97.5% for those with non-normal distribution. The mean serum levels of the hormones in Arab men with prostate cancer were compared with values in healthy age-matched Arab men. There was a significant decrease between the 21-29 years age group and the 70-79 years age group for TT (-38.77%), DHEAS (-70%), ADT (-36%) and FAI (-63.25%), and an increase for SHBG (+64%). The calculated reference ranges are TT (2.73-30.45 nmol/L), SHBG (6.45-65.67 nmol/L), FAI (14.51-180.34), DHEAS (0.9-11.0 micromol/L) and ADT (0.54-4.26 ng/mL). The mean TT, SHBG, DHEAS and ADT in Arab men were significantly lower than those reported for Caucasians especially in the 21-29 years age group. Arab men with

Hormonal changes after localized prostate cancer treatment. Comparison between external beam radiation therapy and radical prostatectomy.

PubMed

Planas, J; Celma, A; Placer, J; Maldonado, X; Trilla, E; Salvador, C; Lorente, D; Regis, L; Cuadras, M; Carles, J; Morote, J

2016-11-01

To determine the influence of radical prostatectomy (RP) and external beam radiation therapy (EBRT) on the hypothalamic pituitary axis of 120 men with clinically localized prostate cancer treated with RP or EBRT exclusively. 120 patients with localized prostate cancer were enrolled. Ninety two patients underwent RP and 28 patients EBRT exclusively. We measured serum levels of luteinizing hormone, follicle stimulating hormone (FSH), total testosterone (T), free testosterone, and estradiol at baseline and at 3 and 12 months after treatment completion. Patients undergoing RP were younger and presented a higher prostate volume (64.3 vs. 71.1 years, p<0.0001 and 55.1 vs. 36.5 g, p<0.0001; respectively). No differences regarding serum hormonal levels were found at baseline. Luteinizing hormone and FSH levels were significantly higher in those patients treated with EBRT at three months (luteinizing hormone 8,54 vs. 4,76 U/l, FSH 22,96 vs. 8,18 U/l, p<0,0001) while T and free testosterone levels were significantly lower (T 360,3 vs. 414,83ng/dl, p 0,039; free testosterone 5,94 vs. 7,5pg/ml, p 0,018). At 12 months FSH levels remained significantly higher in patients treated with EBRT compared to patients treated with RP (21,01 vs. 8,51 U/l, p<0,001) while T levels remained significantly lower (339,89 vs. 402,39ng/dl, p 0,03). Prostate cancer treatment influences the hypothalamic pituitary axis. This influence seems to be more important when patients with prostate cancer are treated with EBRT rather than RP. More studies are needed to elucidate the role that prostate may play as an endocrine organ. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed Central

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-01-01

inhibit the growth of experimental prostate cancers. The efficacy of the antagonist SB-75 in inhibiting androgen-dependent Dunning prostatic carcinoma and the absence of side effects suggest its possible usefulness for the treatment of hormone-sensitive tumors. PMID:1992476

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-02-01

inhibit the growth of experimental prostate cancers. The efficacy of the antagonist SB-75 in inhibiting androgen-dependent Dunning prostatic carcinoma and the absence of side effects suggest its possible usefulness for the treatment of hormone-sensitive tumors.

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

PubMed

Milovanovic, S R; Radulovic, S; Groot, K; Schally, A V

1992-01-01

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.

Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak.

PubMed

Castilla, Carolina; Congregado, Belén; Chinchón, David; Torrubia, Francisco J; Japón, Miguel A; Sáez, Carmen

2006-10-01

Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer.

Apocrine sweat gland obstruction by antiperspirants allowing transdermal absorption of cutaneous generated hormones and pheromones as a link to the observed incidence rates of breast and prostate cancer in the 20th century.

PubMed

McGrath, Kris G

2009-06-01

Breast and prostate cancer share similarities and likely represent homologous cancers in females and males, respectively. The role of hormones such as testosterone and estrogen in carcinogenesis is well established. Despite worldwide research efforts, the pathogenesis of these diseases is largely not well understood. Personal care products containing estrogens or xenoestrogens have raised concern as a breast cancer risk, especially in young African-American women. In the United States (US) there is a parallel rise in the incidence in breast and prostate cancer compared to selected non-hormone dependent tumors. Observed US and global breast and prostate cancer incidence increases were occurring before exogenous hormone replacement and xenoestrogen exposure were commonplace. An unintentional, inadvertent, and long term hormone exposure may occur from transdermal absorption of sex hormones and pheromones (androgens) from axillary apocrine sweat gland obstruction by aluminum-based antiperspirants. The global rise in antiperspirant use parallels rises in breast and prostate cancer incidence and mortality rates. A multi-disciplinary literature based set of evidence is presented on how such a link is possible, to prompt confirmatory investigations in the pursuit of unmet needs in breast and prostate cancer etiology and prevention.

CaM kinase kinase beta-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.

PubMed

Frigo, Daniel E; Howe, Matthew K; Wittmann, Bryan M; Brunner, Abigail M; Cushman, Ian; Wang, Qianben; Brown, Myles; Means, Anthony R; McDonnell, Donald P

2011-01-15

While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens (a) directly increase the expression of a CaMKKβ splice variant and (b) increase functional CaMKKβ protein levels as determined by the phosphorylation of both CaMKI and AMP-activated protein kinase (AMPK), two of CaMKKβ's primary substrates. Importantly, inhibition of the CaMKKβ-AMPK, but not CaMKI, signaling axis in prostate cancer cells by pharmacological inhibitors or siRNA-mediated knockdown blocks androgen-mediated migration and invasion. Conversely, overexpression of CaMKKβ alone leads to both increased AMPK phosphorylation and cell migration. Given the key roles of CaMKKβ and AMPK in the biology of prostate cancer cells, we propose that these enzymes are potential therapeutic targets in prostate cancer. © 2010 AACR.

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

PubMed Central

Ardiani, Andressa; Gameiro, Sofia R.; Kwilas, Anna R.; Donahue, Renee N.; Hodge, James W.

2014-01-01

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT. PMID:25344864

Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy.

PubMed

Suzuki, Taiji; Aihara, Kazuyuki

2013-09-01

These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer.

PubMed

Planas, Jacques; Celma, Ana; Placer, José; Cuadras, Mercè; Regis, Lucas; Gasanz, Carlos; Trilla, Enrique; Salvador, Carlos; Lorente, David; Morote, Juan

2016-12-01

The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients. Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1-73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7-89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6-42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation. After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (< 50 ng/dl). A multivariate analysis was performed to find factors related to testosterone recovery (testosterone >50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan-Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5-22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6-39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029). Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

New Players for Advanced Prostate Cancer and the Rationalisation of Insulin-Sensitising Medication

PubMed Central

Gunter, Jennifer H.; Sarkar, Phoebe L.; Lubik, Amy A.; Nelson, Colleen C.

2013-01-01

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of “old players” for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer. PMID:23573093

New players for advanced prostate cancer and the rationalisation of insulin-sensitising medication.

PubMed

Gunter, Jennifer H; Sarkar, Phoebe L; Lubik, Amy A; Nelson, Colleen C

2013-01-01

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of "old players" for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer.

Proton MRS detects Metabolic Changes in Hormone Sensitive and Resistant Human Prostate Cancer Model CWR22 and CWR22r

PubMed Central

Le, H. Carl; Lupu, Mihaela; Kotedia, Khushali; Rosen, Neal; Solit, David; Koutcher, Jason A.

2010-01-01

17-Allylamino, 17-Demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells (1), has shown promising results against several cancers, including hormone resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as AR (androgen receptor) and HER2/neu, were reduced 4 hours post 17-AAG treatment. Post treatment metabolic changes have also been observed in several tumor cell lines. In this study total choline (t-cho) distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before, 4 hours and 48 hours after a single bolus 17-AAG treatment at 100 mg/kg using proton MRS. Our results show that tumor t-cho levels declined 4 hours after the treatment for CWR22 (P = 0.001) and 48 hours post treatment for CWR22r (P=0.003). Metabolic changes, in particular of t-cho intensity detected by 1H MRSI, are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P=0.01 at 14 days post treatment) and a constant PSA level versus increasing PSA for control CWR22 (P=0.01). Metabolic changes in t-cho by proton MRSI can be used as an early biomarker of response for advanced stage prostate cancer in targeted therapy such as 17-AAG. PMID:19780165

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Mason, Malcolm D; Clarke, Noel W; Anderson, John; Dearnaley, David P; Dwyer, John; Jovic, Gordana; Ritchie, Alastair WS; Russell, J Martin; Sanders, Karen; Thalmann, George N; Bertelli, Gianfilippo; Birtle, Alison J; O'Sullivan, Joe M; Protheroe, Andrew; Sheehan, Denise; Srihari, Narayanan; Parmar, Mahesh KB

2012-01-01

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

PubMed

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

Trichomonas vaginalis infection and risk of advanced prostate cancer.

PubMed

Shui, Irene M; Kolb, Suzanne; Hanson, Christi; Sutcliffe, Siobhan; Rider, Jennifer R; Stanford, Janet L

2016-05-01

The epidemiologic evidence for an association of Trichomonas vaginalis (Tv) with overall prostate cancer is mixed, but some studies suggest Tv may increase risk of more aggressive disease. The aim of this study was to assess whether Tv serostatus is associated with advanced or fatal prostate cancer. A total of 146 men with advanced (metastatic or fatal) prostate cancer and 181 age-matched controls were selected from two prior population-based, case-control studies. Tv serostatus was determined with the same laboratory methods used in previous epidemiologic studies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression to compare Tv serostatus in prostate cancer cases and controls adjusted for potential confounders. The seroprevalence of Tv in controls was 23%. Tv serostatus was not associated with an increased risk of metastatic or fatal prostate cancer (ORs < 1). Our study does not support an increased risk of advanced or fatal prostate cancer in men seropositive for Tv. © 2016 Wiley Periodicals, Inc.

Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen-independent prostate xenografts.

PubMed

Neschadim, Anton; Pritzker, Laura B; Pritzker, Kenneth P H; Branch, Donald R; Summerlee, Alastair J S; Trachtenberg, John; Silvertown, Joshua D

2014-06-01

Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimed at the AR pathway resulting in androgen-independent or hormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for the management of prostate cancer. We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of human H2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgen-independent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98% in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia-induced response. Our data support developing AT-001 for clinical use as an anti-relaxin hormonal therapy for advanced prostate cancer.

Investigative clinical study on prostate cancer part VIII: prolactin hormone and the pituitary-testicular-prostate axis at the time of initial diagnosis and subsequent cluster selection of the patient population after radical prostatectomy.

PubMed

Porcaro, Antonio B; Ghimenton, Claudio; Petrozziello, Aldo; Migliorini, Filippo; Romano, Mario; Sava, Teodoro; Caruso, Beatrice; Cocco, Claudio; Antoniolli, Stefano Zecchinini; Lacola, Vincenzo; Rubilotta, Emanuele; Monaco, Carmelo; Comunale, Luigi

2012-04-01

To evaluate the prolactin hormone (PRL) physiopathology along the pituitary testicular prostate axis at the time of initial diagnosis of prostate cancer and the subsequent cluster selection of the patient population after radical prostatectomy in relation to clinical and pathological variables. Ninety-two operated prostate cancer patients were retrospectively reviewed. No patient had previously received hormonal treatment. The investigated variables included PRL, follicle stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), total prostate specific antigen (PSA), percentage of positive cores at transrectal ultrasound scan biopsy (TRUSB) (P+), biopsy Gleason score (bGS), pathology Gleason score (pGS), estimated tumor volume in relation to percentage of prostate volume (V+), overall prostate weight (Wi) and age. Empirical PRL correlations and multiple linear predictions were investigated along the pituitary testis prostate axis in the different groups of the prostate cancer population and clustered according to pT (2a/b, 3a, 3b/4) status. The patient population was classified according to the log(10) PRL/V+ ratio and clustered as follows: group A (log(10) PRL/V+ ≤1.5), B (1.5< log(10)PRL/V+ ≤2.0) and C (log(10) PRL/V+ >2.0). Simple linear regression analysis of V+ predicting PRL was computed for assessing the clustered model and analysis of variance was performed for assessing significant differences between the groups. PRL was independently predicted by FSH (p=0.01), LH (p=0.008) and P+ (p=0.06) in low-stage prostate cancer (pT2a/b). Interestingly, PRL was independently predicted by LH (p=0.03) and FSH, TT, FT, PSA, bGS, pGS, V+, Wi and age (all at p=0.01) in advanced stage-disease (pT3b/4). V+ was also significantly correlated (r=0.47) and predicted by P+ (p<0.0001) in the prostate cancer population. PRL was significantly correlated and predicted by V+ when the patient population was clustered according to the log

Illicit use of androgens and other hormones: recent advances.

PubMed

Kanayama, Gen; Pope, Harrison G

2012-06-01

To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

An Update on Triptorelin: Current Thinking on Androgen Deprivation Therapy for Prostate Cancer.

PubMed

Merseburger, Axel S; Hupe, Marie C

2016-07-01

Androgen deprivation therapy (ADT) is the mainstay palliative treatment for men with locally advanced and metastatic prostate cancer, and aims to reduce testosterone to levels obtained by surgical castration. Use of gonadotropin-releasing hormone (GnRH) agonists predominates among the ADT options. The GnRH agonist, triptorelin is a first-line hormonal therapy that has demonstrated efficacy and safety in clinical trials of patients with locally advanced non-metastatic or metastatic disease. Sustained-release 1-, 3- and 6-month formulations of triptorelin, administered intramuscularly or subcutaneously, have been developed to provide improved flexibility and convenience for the patient. Head-to-head studies of GnRH agonists are lacking in the field of prostate cancer. Despite the inevitable progression to castration-resistant prostate cancer (CRPC) in most patients receiving ADT, monitoring of testosterone levels needs to improve in routine practice and physicians should not overlook the benefits of continued ADT in their patients when introducing one of the various new treatment options for CRPC. For improved survival outcomes, there remains a need to tailor ADT treatment regimens, novel hormonal agents and chemotherapy according to the individual patient with advanced prostate cancer.

The Diagnosis and Treatment of Prostate Cancer: A Review.

PubMed

Litwin, Mark S; Tan, Hung-Jui

2017-06-27

Prostate cancer is the most common cancer diagnosis made in men with more than 160 000 new cases each year in the United States. Although it often has an indolent course, prostate cancer remains the third-leading cause of cancer death in men. When prostate cancer is suspected, tissue biopsy remains the standard of care for diagnosis. However, the identification and characterization of the disease have become increasingly precise through improved risk stratification and advances in magnetic resonance and functional imaging, as well as from the emergence of biomarkers. Multiple management options now exist for men diagnosed with prostate cancer. Active surveillance (the serial monitoring for disease progression with the intent to cure) appears to be safe and has become the preferred approach for men with less-aggressive prostate cancer, particularly those with a prostate-specific antigen level of less than 10 ng/mL and Gleason score 3 + 3 tumors. Surgery and radiation continue to be curative treatments for localized disease but have adverse effects such as urinary symptoms and sexual dysfunction that can negatively affect quality of life. For metastatic disease, chemotherapy as initial treatment now appears to extend survival compared with androgen deprivation therapy alone. New vaccines, hormonal therapeutics, and bone-targeting agents have demonstrated efficacy in men with metastatic prostate cancer resistant to traditional hormonal therapy. Advances in the diagnosis and treatment of prostate cancer have improved the ability to stratify patients by risk and allowed clinicians to recommend therapy based on cancer prognosis and patient preference. Initial treatment with chemotherapy can improve survival compared with androgen deprivation therapy. Abiraterone, enzalutamide, and other agents can improve outcomes in men with metastatic prostate cancer resistant to traditional hormonal therapy.

Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.

PubMed

Li, Yirong; Ligr, Martin; McCarron, James P; Daniels, Garrett; Zhang, David; Zhao, Xin; Ye, Fei; Wang, Jinhua; Liu, Xiaomei; Osman, Iman; Mencher, Simon K; Lepor, Hebert; Wang, Long G; Ferrari, Anna; Lee, Peng

2011-07-01

The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.

The feasibility and safety of high-intensity focused ultrasound combined with low-dose external beam radiotherapy as supplemental therapy for advanced prostate cancer following hormonal therapy.

PubMed

Wu, Rui-Yi; Wang, Guo-Min; Xu, Lei; Zhang, Bo-Heng; Xu, Ye-Qing; Zeng, Zhao-Chong; Chen, Bing

2011-05-01

The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound (HIFU) combined with (+) low-dose external beam radiotherapy (LRT) as supplemental therapy for advanced prostate cancer (PCa) following hormonal therapy (HT). Our definition of HIFU+LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy (CRT). We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU+LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU+LRT treatment. There were significant differences among four groups with regard to overall survival (OS) and disease-specific survival (DSS) curves (P = 0.018 and 0.015). Further comparison between each pair of groups suggested that the long-term DSS of the HIFU+LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU+LRT group and the CRT group. Multivariable Cox's proportional hazard model showed that both HIFU+LRT and CRT were independently associated with DSS (P = 0.001 and 0.035) and had protective effects with regard to the risk of death. Compared with CRT, HIFU+LRT significantly decreased incidences of radiation-related late gastrointestinal (GI) and genitourinary (GU) toxicity grade ≥ II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and regional lymph node metastases after HT. As an alternative to CRT, HIFU+LRT showed good efficacy and better safety.

Practical differences between luteinizing hormone-releasing hormone agonists in prostate cancer: perspectives across the spectrum of care

PubMed Central

Meani, Davide; Solarić, Mladen; Visapää, Harri; Rosén, Rose-Marie; Janknegt, Robert; Soče, Majana

2017-01-01

Background: Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists is well established for the treatment of men with metastatic prostate cancer. As clear differences in efficacy, safety, or tolerability between the available LHRH agonists are lacking, the healthcare management team needs to look to practical differences between the formulations when selecting therapy for their patients. Moreover, as the economic burden of prostate cancer rises alongside earlier diagnosis and improved survival, the possibility for cost savings by using products with specific features is growing in importance. Methods: A review was conducted to summarize the information on the different LHRH agonist formulations currently available and offer insight into their relative benefits and disadvantages from the perspectives of physicians, a pharmacist, and a nurse. Results: The leuprorelin acetate and goserelin acetate solid implants have the advantage of being ready to use with no requirement for refrigeration, whereas powder and microsphere formulations have to be reconstituted and have specific storage or handling constraints. The single-step administration of solid implants, therefore, has potential to reduce labor time and associated costs. Dosing frequency is another key consideration, as administering the injection provides an opportunity for face-to-face interaction between the patient and healthcare professionals to ensure therapy is optimized and give reassurance to patients. Prostate cancer patients are reported to prefer 3- or 6-monthly dosing, which aligns with the monitoring frequency recommended in European Association of Urology guidelines and has been shown to result in reduced annual costs compared with 1-month formulations. Conclusions: A number of practical differences exist between the different LHRH agonist preparations available, which may impact on clinical practice. It is important for healthcare providers to be aware and

Is whole gland salvage cryotherapy effective as palliative treatment of haematuria in patients with locally advanced prostate cancer? Results of a preliminary case series

PubMed Central

Mucciardi, Giuseppe; Galì, Alessandro; Pappalardo, Rosa; Lembo, Francesco; Anastasi, Giuseppina; Butticè, Salvatore; Ascenti, Giorgio; Lugnani, Franco

2015-01-01

Objectives: Locally advanced prostate cancer may cause several complications such as haematuria, bladder outlet obstruction, and renal failure due to the ureteral obstruction. Various treatments have been suggested, including radiotherapy, antifibrinolytics, bladder irrigation with alum solution, transurethral surgery and angioembolization, none of which have proven effectiveness. In the last years cryoablation has become a valid therapeutic option for prostate cancer. In our experience we used this ‘new’ technique as haemostatic therapy. Methods: We selected four patients with gross haematuria affected by locally advanced hormone refractory prostate cancer, who had already been treated with primary radiotherapy. We used third-generation cryotherapy: under ultrasonographic guidance, we inserted six cryoprobes, two in each of the vascular pedicles reaching at least −60°C, and three thermometers. We then induced two freeze–thaw cycles. Results: After the operation the haematuria stopped in all patients and at 9-month follow up we observed a mean of four red cells (range three to five) in the urinary sediment with no evidence of bacteriuria. Prostate volume, prostate-specific antigen and postmicturition residue were significantly reduced. Qmax improved significantly too. Conclusion: Our experience has given us good results with minimal intra- and postoperative complications. We think that haemostatic cryotherapy as a palliative approach for locally advanced prostate cancer could represent a valid treatment option and more consideration could be given to its use. PMID:26425138

[Hormonal and metabolic effects of drinking mineral water and phytoaeronisation in experimental prostatitis].

PubMed

Polushina, N D; Agaev, A A; Shchelkunov, A V; Eseneev, S M

2004-01-01

Prostatitis modelled in 53 Wistar male rats (300-350 body mass) 7 days after its induction was treated with mineral water "Essentuki N 17" (MW) which was taken in a dose 1.5-2 ml per 100 g body mass for 23-24 days. In addition, some animals received phytoaeroionisation (PAI) with solution of essential oils of mint, sage and lavender. Prostatitis is associated with disorders in prostatic tissue, levels of sex hormones (testosterone, prolactin, FSH, LH), a rise in total cholesterol, glucose. Watering of animals with MW and PAI raised blood insulin, hydrocortisone and testosterone, normalized blood glucose and cholesterol. There was a correlation between blood levels of hydrocortisone and testosterone.

Concept and viability of androgen annihilation for advanced prostate cancer.

PubMed

Mohler, James L

2014-09-01

There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer.

PubMed

Dall'Era, Marc A; Lo, Mary J; Chen, Jaclyn; Cress, Rosemary; Hamilton, Ann S

2018-05-01

To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption

Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

PubMed Central

Shepherd, Andrew J.; Mickle, Aaron D.; Kadunganattil, Suraj; Hu, Hongzhen; Mohapatra, Durga P.

2018-01-01

Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained activation of TRPV1, in the absence of any exogenous channel agonist, and is dependent on the expression of the type-1 parathyroid hormone receptor (PTH1), as well as on downstream phosphorylation of the channel by protein kinase C (PKC). Accordingly, local administration of specific small-molecule antagonists of TRPV1 to mouse hindpaws after the development of PTHrP-induced mechanical hypersensitivity led to its significant attenuation. Collectively, our findings suggest that PTHrP/PTH1-mediated flow activation of TRPV1 channel contributes at least in part to the development and maintenance of peripheral mechanical pain hypersensitivity, and could therefore constitute a mechanism for nociceptor sensitization in the context of metastatic bone

Complex relationship between sex hormones, insulin resistance and leptin in men with and without prostatic disease.

PubMed

Grosman, Halina; Fabre, Bibiana; Lopez, Miguel; Scorticati, Carlos; Lopez Silva, Maximiliano; Mesch, Viviana; Mazza, Osvaldo; Berg, Gabriela

2016-01-01

To assess sex hormones, leptin and insulin-resistance in men with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and to study associations between androgens and histologic score of prostate tissue in PCa. Two hundred ten men older than 45 years selected from 2906 participants of a population screening for PCa were studied: 70 with PCa, 70 with BPH and 70 controls (CG), matched by body mass index and age. Insulin, IGF-1, PSA, leptin, total, free (fT) and bioavailable testosterone (bT) and estradiol were measured. Each group was subdivided into two subgroups considering the presence of metabolic syndrome (MS); androgens and leptin levels were analyzed in the subgroups. Prostate cancer and BPH patients presented higher total, fT and bT levels than CG. IGF-1, insulin and HOMA index were higher in BPH than in the other two groups. PCa presented higher leptin [median (range) 6.5 (1.3-28.0) versus 4.8 (1.1-12.3) ng/ml; p < 0.01] and estradiol [median (range) 37.0 (20-90) versus 29.0 (20-118) pg/ml; p = 0.025] levels than CG. After dividing men considering the presence of MS, leptin was higher and total testosterone was lower in MS patients in all the groups. It was observed a coexistence of an altered hormone profile with increased sex hormones and leptin in PCa patients, in accordance with the new perspective of PCa pathogenesis.

Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer.

PubMed

Gunlusoy, Bulent; Ceylan, Yasin; Koskderelioglu, Aslı; Gedizlioglu, Muhtesem; Degirmenci, Tansu; Ortan, Pınar; Kozacioglu, Zafer

2017-05-01

To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer. From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function. Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy. ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary prevention of hormone refractory prostate cancer in Lobund-Wistar rats: a review of studies in a relevant animal model.

PubMed

Pollard, Morris; Suckow, Mark A

2006-12-01

Lobund-Wistar (LW) rats, which have high testosterone levels, are predisposed to develop hormone-refractory prostate cancer (HRPC) spontaneously and by methylnitrosourea (MNU) induction, and the development of HRPC progresses through 2 stages. This paper reviews several studies in which LW rats were placed on soy-containing diets and were evaluated for development of either spontaneous or MNU-induced prostate cancer. The premalignant, testosterone-dependent stage is inhibited by testosterone deprivation. In the absence of testosterone deprivation, tumorigenesis progresses spontaneously to the testosterone-independent refractory stage. In LW rats: moderate caloric restriction prevented development of spontaneous prostate cancer; dietary 4-hydroxyphenylretinamide prevented MNU-induced prostate cancer; and dietary supplementation with soy protein isolate with high isoflavones prevented spontaneous and induced tumors and led to moderate reduction of serum testosterone. In rats 12 mo of age and younger, changing from the control diet to the soy+isoflavone diet significantly prevented progression of spontaneous tumors to the refractory stage of disease. Tumors that developed spontaneously and after MNU induction showed similar developmental stages and morphology, but MNU-induced tumors had shorter latency periods before development. The accumulated data indicate that soy-based diets are effective in the prevention of prostate cancer.

Elevated serum progastrin-releasing peptide (31-98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer.

PubMed

Yashi, Masahiro; Nukui, Akinori; Kurokawa, Shinsuke; Ochi, Masanori; Ishikawa, Shinya; Goto, Kentaro; Kobayashi, Yutaka; Muraishi, Osamu; Tokue, Akihiko

2003-09-01

The neuroendocrine (NE) pathway has been attracting attention as a mechanism for the androgen-independent progression because the neuropeptide provokes tumor growth and inhibits apoptosis under androgen-deprived milieu in prostate cancer cells. On the basis that serum progastrin-releasing peptide (ProGRP) is elevated in patients with advanced disease stage, we examined the prognostic value of the neuropeptide. Serum ProGRP status was determined with an enzyme-linked immunosorbent assay (ELISA) in 460 men with benign and malignant prostatic diseases, chronic renal failure, and healthy controls. Seventy patients with metastatic prostate cancer including four patients (5.7%) with NE carcinoma who underwent hormonal therapy were enrolled in the prognostic analyses by Cox proportional hazards model. The serum status steadily shifted toward predominant expression of ProGRP with the progression of prostate cancer into metastatic and androgen-independent stages. Univariate analysis revealed that the deteriorated performance status (PS) and extent of bony disease (EOD), and high serum alkaline phosphatase (ALP), serum ProGRP, and nadir prostate-specific antigen (PSA) levels were associated with a lower progression-free survival (PFS) rate (P < 0.005). Multivariate analysis demonstrated that PS, serum ProGRP, and nadir PSA held an independent predictive value for PFS (P < 0.05), and all correlated with bone-related factors. Serum ProGRP was the most significant predictor among pre-treatment factors in this model (P = 0.0094). The neuropeptide precursor ProGRP is a distinct serum marker that is useful to know the NE milieu and provides prognostic information in patients with advanced prostate cancer. Standard therapy for metastatic prostate cancer may make progress when further studies will clarify the causative link between serum ProGRP level and androgen-independent disease progression. Copyright 2003 Wiley-Liss, Inc.

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers.

PubMed

Zhou, Cindy Ke; Stanczyk, Frank Z; Hafi, Muhannad; Veneroso, Carmela C; Lynch, Barlow; Falk, Roni T; Niwa, Shelley; Emanuel, Eric; Gao, Yu-Tang; Hemstreet, George P; Zolfghari, Ladan; Carroll, Peter R; Manyak, Michael J; Sesterhenn, Isabell A; Levine, Paul H; Hsing, Ann W; Cook, Michael B

2017-12-01

Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (<7 vs ≥7) and race (European American vs. African American). We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak

Advances in Imaging in Prostate and Bladder Cancer.

PubMed

Srivastava, Abhishek; Douglass, Laura M; Chernyak, Victoria; Watts, Kara L

2017-09-01

Recent advancements in urologic imaging techniques aim to improve the initial detection of urologic malignancies and subsequent recurrence and to more accurately stage disease. This allows the urologist to make better informed treatment decisions. In particular, exciting advances in the imaging of prostate cancer and bladder cancer have recently emerged including the use of dynamic, functional imaging with MRI and PET. In this review, we will explore these imaging modalities, in addition to new sonography techniques and CT, and how they hope to improve the diagnosis and management of prostate and bladder cancer.

Prognostic Factors for Hormone Sensitive Metastatic Prostate Cancer: Impact of Disease Volume

PubMed

Alhanafy, Alshimaa Mahmoud; Zanaty, Fouad; Ibrahem, Reda; Omar, Suzan

2018-04-27

Background and Aim: The optimal management of metastatic hormone-sensitive prostate cancer has been controversial in recent years with introduction of upfront chemohormonal treatment based on results of several Western studies. This changing landscape has renewed interest in the concept “disease volume”, the focus of the present study is the Egyptian patients. Methods: Patients with hormone sensitive metastatic prostate cancer presenting at Menoufia University Hospital, Egypt, during the period from June 2013 to May 2016, were enrolled. All received hormonal treatment. Radiologic images were evaluated and patients were stratified according to their disease volume into high or low, other clinical and pathological data that could affect survival also being collected and analyzed. Results: A total of 128 patients were included, with a median age of 70 years (53.9% ≥70). About 46% had co-morbidities, 62% having high volume disease. During the median follow up period of 28 months about half of the patients progressed and one third received chemotherapy. On univariate analysis, disease volume, performance status (PS), prostate specific antigen level (PSA) and presence of pain at presentation were identified as factors influencing overall survival. Multivariate analysis revealed the independent predictor factors for survival to be PS, PSA and disease volume. The median overall survival with 27 months was high volume versus 49 with low volume disease (hazard ratio 2.1; 95% CI 1.2 - 4.4; P=0.02). Median progression free survival was 19 months in the high volume, as compared with 48 months in the low volume disease patients (hazard ratio, 2.44; 95% CI, 1.42 – 7.4; P=0.009). Conclusions: Disease volume is a reliable predictor of survival which should be incorporated with other important factors as; patient performance status and comorbidities in treatment decision-making. Creative Commons Attribution License

Gynecomastia due to hormone therapy for advanced prostate cancer: a report of ten surgically treated cases and a review of treatment options.

PubMed

Prezioso, Domenico; Piccirillo, Giuseppe; Galasso, Raffaele; Altieri, Vincenzo; Mirone, Vincenzo; Lotti, Tullio

2004-01-01

Gynecomastia is an abnormal increase in the volume of the male breast that is generally considered to be due to an increased estrogen/androgen ratio. Pathological causes of gynecomastia include organic diseases and therapy, such as the administration of estrogens and antiandrogens, which alter the ratio of circulating hormones. Hormone therapy for prostate cancer is generally well tolerated but often accompanied by the occurrence of gynecomastia and breast pain or tenderness. The increased use of antiandrogens as monotherapy is leading to an increase in the number of patients affected by gynecomastia. Treatments are available to alleviate or prevent the development of gynecomastia, including medical treatment with antiestrogens and aromatase inhibitors. Alternatively, mastectomy with excision of the gland, liposuction or an association of the two techniques have proved to be effective. Radiation therapy may provide effective relief from the breast pain associated with gynecomastia. In this paper we show the good results of mastectomy performed with a lower semicircular periareolar incision in men suffering from gynecomastia due to antiandrogen therapy for inoperable prostate cancer. In addition, we present a review of the various techniques used for the treatment of gynecomastia. During the period from September 1998 to May 2001, 10 patients receiving hormone treatment for metastatic or inoperable prostatic cancer were selected for the study if they had breast pain and bilateral gynecomastia. Five of these patients had been offered prophylactic radiotherapy before treatment but refused, while the remaining five patients had refused radiotherapy after hormone treatment. These patients were therefore given the option of surgical treatment. Before surgery all patients underwent clinical and ultrasound examination of the breast. All surgical samples were examined histopathologically. During follow-up clinical examinations were carried out one week, one month, six

Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer.

PubMed

Steinberg, Michael

2009-01-01

Prostate cancer is the most commonly diagnosed cancer among men. Treatment can include surgery, radiation, chemotherapy, or hormonal manipulation. Gonadotropin-releasing hormone (GnRH) analogues are used to manage prostate cancer by desensitizing the stimulus to synthesize and release gonadotropins, such as luteinizing hormone (LH), which stimulate the synthesis and release of androgens, in turn stimulating the growth of prostate cancer cells. Although effective, these agents have limitations, such as a flare-up of cancer symptoms within the first 2 weeks of starting the drug. This article reviews the pharmacology, pharmacokinetic and pharmacodynamic characteristics, and clinical data available on the newly approved drug degarelix for use in treating prostate cancer. A search of the medical literature was performed in January 2009 with the databases MEDLINE and EMBASE (1950-present) and International Pharmaceutical Abstracts (1970-November 2008) using the terms degarelix and FE200486; follow-up searches using the same strategy were conducted in May 2009 and August 2009. Additional sources were identified by scanning available references and online journals and textbooks. GnRH antagonists, such as degarelix, offer clinicians another means to reduce the level of circulating androgens and limit this growth stimulus directed at malignant prostate tissue. Degarelix has been shown in animal studies to antagonize GnRH receptors in the pituitary gland, resulting in a significant reduction in circulating LH and a subsequent decrease in the synthesis of testosterone. Pharmacokinetic analysis suggests that upon subcutaneous administration, degarelix forms a gel depot, from which the drug then distributes to the rest of the body in a first-order manner. A Phase II study of the effect of degarelix in 187 men with prostate cancer found a loading dose of 240 mg to be not significantly better than 200 mg in reducing serum testosterone concentrations to < or =0.5 ng/mL within 3

A pilot study on understanding the journey of advanced prostate cancer patients.

PubMed

Wagholikar, Amol; Fung, Maggie; Nelson, Colleen

2011-01-01

To understand the journey of advanced prostate cancer patients for supporting development of an innovative patient journey browser. Prostate cancer is one of the common cancers in Australia. Due to the chronic nature of the disease, it is important to have effective disease management strategy and care model. Multi-disciplinary care is a well-proven approach for chronic disease management. The Multi-disciplinary team (MDT) can function more effectively if all the required information is available for the clinical decision support. The development of innovative technology relies on an accurate understanding of the advanced prostate cancer patient's journey over a prolonged period. This need arises from the fact that advanced prostate cancer patients may follow various treatment paths and change their care providers. As a result of this, it is difficult to understand the actual sources of patient's clinical records and their treatment patterns. The aim of the research is to understand variable sources of clinical records, treatment patterns, alternative therapies, over the counter (OTC) medications of advanced prostate cancer patients. This study provides better and holistic understanding of advanced prostate cancer journey. The study was conducted through an on-line survey developed to seek and analyse the responses from the participants. The on-line questionnaire was carefully developed through consultations with the clinical researchers at the Australian Prostate Cancer Research Centre-Queensland, prostate cancer support group representatives and health informaticians at the Australian E-Health Research Centre. The non-identifying questionnaire was distributed to the patients through prostate cancer support groups in Queensland, Australia. The pilot study was carried out between August 2010 and December 2010. The research made important observations about the advanced prostate cancer journey. It showed that General Practitioner (GP) was the common source of

Androgen receptor signaling and mutations in prostate cancer

PubMed Central

Koochekpour, Shahriar

2010-01-01

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent (AI) progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer (PCa). Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues. PMID:20711217

Molecular Markers of Estrogen Metabolism and Progression From High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) to Prostate Cancer

DTIC Science & Technology

2006-02-01

recruitment. Adipocytes (i.e., fat cells) regulate insulin sensitivity , steroid hormone metabolism, inflammatory responses , and release leptin and other...diabetes and insulin sensitivity on prostate cancer risk. • Less tangible, but no less significant, this study initiated a prostate cancer...proliferator-activated receptr alpha (PPARalpha) gene is associated with lower body mass index in patients with non- insulin -dependent diabetes mellitus

The prostate after castration and hormone replacement in a rat model: structural and ultrastructural analysis

PubMed Central

Felix-Patrício, Bruno; Miranda, Alexandre F.; Medeiros, Jorge L.; Gallo, Carla B. M.; Gregório, Bianca M.; de Souza, Diogo B.; Costa, Waldemar S.; Sampaio, Francisco J. B.

2017-01-01

ABSTRACT Purpose: To evaluate if late hormonal replacement is able to recover the prostatic tissue modified by androgenic deprivation. Materials and Methods: 24 rats were assigned into a Sham group; an androgen deficient group, submitted to bilateral orchiectomy (Orch); and a group submitted to bilateral orchiectomy followed by testosterone replacement therapy (Orch+T). After 60 days from surgery blood was collected for determination of testosterone levels and the ventral prostate was collected for quantitative and qualitative microscopic analysis. The acinar epithelium height, the number of mast cells per field, and the densities of collagen fibers and acinar lumen were analyzed by stereological methods under light microscopy. The muscle fibers and types of collagen fibers were qualitatively assessed by scanning electron microscopy and polarization microscopy. Results: Hormone depletion (in group Orch) and return to normal levels (in group Orch+T) were effective as verified by serum testosterone analysis. The androgen deprivation promoted several alterations in the prostate: the acinar epithelium height diminished from 16.58±0.47 to 11.48±0.29μm; the number of mast cells per field presented increased from 0.45±0.07 to 2.83±0.25; collagen fibers density increased from 5.83±0.92 to 24.70±1.56%; and acinar lumen density decreased from 36.78±2.14 to 16.47±1.31%. Smooth muscle was also increased in Orch animals, and type I collagen fibers became more predominant in these animals. With the exception of the densities of collagen fibers and acinar lumen, in animals receiving testosterone replacement therapy all parameters became statistically similar to Sham. Collagen fibers density became lower and acinar lumen density became higher in Orch+T animals, when compared to Sham. This is the first study to demonstrate a relation between mast cells and testosterone levels in the prostate. This cells have been implicated in prostatic cancer and benign hyperplasia

The prostate after castration and hormone replacement in a rat model: structural and ultrastructural analysis.

PubMed

Felix-Patrício, Bruno; Miranda, Alexandre F; Medeiros, Jorge L; Gallo, Carla B M; Gregório, Bianca M; Souza, Diogo B; Costa, Waldemar S; Sampaio, Francisco J B

2017-01-01

To evaluate if late hormonal replacement is able to recover the prostatic tissue modified by androgenic deprivation. 24 rats were assigned into a Sham group; an androgen deficient group, submitted to bilateral orchiectomy (Orch); and a group submitted to bilateral orchiectomy followed by testosterone replacement therapy (Orch+T). After 60 days from surgery blood was collected for determination of testosterone levels and the ventral prostate was collected for quantitative and qualitative microscopic analysis. The acinar epithelium height, the number of mast cells per field, and the densities of collagen fibers and acinar lumen were analyzed by stereological methods under light microscopy. The muscle fibers and types of collagen fibers were qualitatively assessed by scanning electron microscopy and polarization microscopy. Hormone depletion (in group Orch) and return to normal levels (in group Orch+T) were effective as verified by serum testosterone analysis. The androgen deprivation promoted several alterations in the prostate: the acinar epithelium height diminished from 16.58±0.47 to 11.48±0.29μm; the number of mast cells per field presented increased from 0.45±0.07 to 2.83±0.25; collagen fibers density increased from 5.83±0.92 to 24.70±1.56%; and acinar lumen density decreased from 36.78±2.14 to 16.47±1.31%. Smooth muscle was also increased in Orch animals, and type I collagen fibers became more predominant in these animals. With the exception of the densities of collagen fibers and acinar lumen, in animals receiving testosterone replacement therapy all parameters became statistically similar to Sham. Collagen fibers density became lower and acinar lumen density became higher in Orch+T animals, when compared to Sham. This is the first study to demonstrate a relation between mast cells and testosterone levels in the prostate. This cells have been implicated in prostatic cancer and benign hyperplasia, although its specific role is not understood

Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer.

PubMed

Gershman, Boris; Shui, Irene M; Stampfer, Meir; Platz, Elizabeth A; Gann, Peter H; Sesso, Howard L; DuPre, Natalie; Giovannucci, Edward; Mucci, Lorelei A

2014-04-01

Sex hormones play an important role in the growth and development of the prostate, and low androgen levels have been suggested to carry an adverse prognosis for men with prostate cancer (PCa). To examine the association between prediagnostic circulating sex hormones and lethal PCa in two prospective cohort studies, the Physicians' Health Study (PHS) and the Health Professionals Follow-up Study (HPFS). We included 963 PCa cases (700 HPFS; 263 PHS) that provided prediagnostic blood samples, in 1982 for PHS and in 1993-1995 for HPFS, in which circulating sex hormone levels were assayed. The primary end point was lethal PCa (defined as cancer-specific mortality or development of metastases), and we also assessed total mortality through March 2011. We used Cox proportional hazards models to evaluate the association of prediagnostic sex hormone levels with time from diagnosis to development of lethal PCa or total mortality. PCa cases were followed for a mean of 12.0±4.9 yr after diagnosis. We confirmed 148 cases of lethal PCa and 421 deaths overall. Using Cox proportional hazard models, we found no significant association between quartile of total testosterone, sex hormone binding globulin (SHBG), SHBG-adjusted testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, or estradiol and lethal PCa or total mortality. In subset analyses stratified by Gleason score, TNM stage, age, and interval between blood draw and diagnosis, there was also no consistent association between lethal PCa and sex hormone quartile. We found no overall association between prediagnostic circulating sex hormones and lethal PCa or total mortality. Our null results suggest that reverse causation may be responsible in prior studies that noted adverse outcomes for men with low circulating androgens. Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Docosahexaenoic acid inhibits the growth of hormone-dependent prostate cancer cells by promoting the degradation of the androgen receptor.

PubMed

Hu, Zhimei; Qi, Haixia; Zhang, Ruixue; Zhang, Kun; Shi, Zhemin; Chang, Yanan; Chen, Linfeng; Esmaeili, Mohsen; Baniahmad, Aria; Hong, Wei

2015-09-01

Epidemiological and preclinical data have demonstrated the preventative effects of ω-3 polyunsaturated fatty acids, including docosahexaenoic acid (DHA), on prostate cancer. However, there are inconsistencies in these previous studies and the underlying mechanisms remain to be elucidated. In the present study, the androgen receptor (AR), which is a transcription factor involved in cell proliferation and prostate carcinogenesis, was identified as a target of DHA. It was revealed that DHA inhibited hormone‑dependent growth of LNCaP prostate cancer cells. Reverse transcription-quantitative polymerase chain reaction analysis revealed that treatment with DHA caused no alteration in the transcribed mRNA expression levels of the AR gene. However, immunoblotting revealed that this treatment reduces the protein expression level of the AR. The androgen‑induced genes were subsequently repressed by treatment with DHA. It was demonstrated that DHA exhibits no effect on the translation process of the AR, however, it promotes the proteasome‑mediated degradation of the AR. Therefore, the present study provided a novel mechanism by which DHA exhibits an inhibitory effect on growth of prostate cancer cells.

Cell Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer

DTIC Science & Technology

2016-12-01

biochemical and biologic assay systems. The final specific aim was tol examine the ability of the bispecific antibody to perturb the growth of prostate ...designated by other documentation. TITLE: Cell-Penetrating Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate ...Bispecific Antibodies for Targeting Oncogenic Transcription Factors in Advanced Prostate Cancer Michael Lilly, MD Richard Weisbart, MD Medical

New advances in focal therapy for early stage prostate cancer.

PubMed

Tay, Kae Jack; Schulman, Ariel A; Sze, Christina; Tsivian, Efrat; Polascik, Thomas J

2017-08-01

Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years. Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms 'focal therapy', 'focal ablation', 'partial ablation', 'targeted ablation', 'image guided therapy' and 'prostate cancer'. Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific-membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development.

Photodynamic therapy using hemagglutinating virus of Japan envelope (HVJ-E): a novel therapeutic approach for the treatment of hormone antagonistic prostate cancer

NASA Astrophysics Data System (ADS)

Inai, Mizuho; Yamauchi, Masaya; Honda, Norihiro; Hazama, Hisanao; Tachikawa, Shoji; Nakamura, Hiroyuki; Nishida, Tomoki; Yasuda, Hidehiro; Kaneda, Yasufumi; Awazu, Kunio

2015-03-01

Traditional treatment options for prostate cancer are insufficient to cure advanced drug-resistant prostate cancer. Thus, as an alternative form of cancer therapy, photodynamic therapy (PDT) has become the main subject of intense investigation as a possible treatment modality. In this study, ultraviolet-inactivated viral vector, called hemagglutinating virus of Japan envelope (HVJ-E) was utilized to establish an effective delivery system for photosensitizer. Lipidated protoporphyrin IX (PpIX lipid) was inserted in HVJ-E by centrifugation to create a new drug delivering system that allows selective accumulation of photosensitizers in cancer cells. To study in vitro drug release mechanism of porphyrus envelope, the ultra-high voltage electron microscope tomography was applied. Next, to evaluate the photodynamic efficiency of porphyrus envelope for hormone antagonistic prostate cancer cells (PC-3), uptake of porphyrus envelope derived PpIX lipid and PpIX induced from exogenously administered precursor of 5-aminolevulinic acid hydrochloride (5-ALA) were compared by measuring fluorescence intensity of PpIX. Finally, to evaluate the efficacy of porphyrus envelope-PDT, laser light at a wavelength of 405 nm was irradiated to PC-3 cells. As a result, incorporation of porphyrus envelope-derived PpIX lipid occurred via membrane fusion, giving the highest fluorescence intensity when compared to 5-ALA-induced PpIX. Also, results from PDT experiment revealed the 28.6 × 103-fold and 206-fold increase in therapeutic efficacy when compared to those of PDT using 5-ALA induced PpIX and PpIX lipid, respectively. Our findings suggest how porphyrus envelope can induce efficient accumulation of PpIX lipid, which can enhance the therapeutic efficacy of PDT against hormone antagonistic prostate cancer.

The 5th Conference on Asian Trends in Prostate Cancer Hormone Therapy.

PubMed

Akaza, Hideyuki; Moore, Malcolm A; Chang, Shu-Jen; Cheng, Christopher; Choi, Han Yong; Esuvaranathan, Kesavan; Hinotsu, Shiro; Hong, Sung-Joon; Kim, Choung-Soo; Kim, Wun-Jae; Murai, Masaru; Naito, Seiji; Soebadi, Doddy; Song, Jae-Mann; Umbas, Rainy; Usami, Michiyuki; Xia, Shujie; Yang, Chi-Rei

2007-01-01

The Conference on Asian Trends in Prostate Cancer Hormone Therapy is an annual forum for Asian urologists now in its 5th year. The 2006 conference, held in Bali, Indonesia, was attended by 27 leading urologic oncologists from China, Indonesia, Japan, Korea, Singapore, and Taiwan and featured a packed program of presentations and discussions on a wide range of topics such as relationships among clinicians and the newly opened Asia Regional Office for Cancer Control of the International Union Against Cancer (UICC), detection rates of prostate cancer by biopsy in each of the 6 Asian countries, and favored treatment modalities for hormone-refractory prostate cancer (HRPC) in each country. The first session of the conference kicked off with a keynote lecture entitled "Activities of the UICC ARO". UICC's new office will be the nerve center for its activities in the Asia region. Along with the Asian Pacific Organization for Cancer Prevention (APOCP), UICC aims to shift the focus of attention to cancer control. As such APOCP's long-running publication the APJCP is to be re-launched as the Asian Pacific Journal of Cancer Control. Although UICC is primarily concerned with cancer, several risk factors for cancer are common also to other non-communicable diseases such as diabetes and heart disease, and an important strategy is to implement measures to control these various pathologic conditions as a whole. Apart from contributing to an Asian prostate cancer registry the UICC-ARO will provide training courses, working groups, and assistance in collecting and processing data. The keynote lecture was followed by a roundtable discussion on possible ways in which clinicians from each Asian country can work with UICC. A number of suggestions were put forth including better registration, epidemiology research, possible implementation of UICC prostate cancer guidelines, early detection and screening, and roles of diet and phytotherapy. The underlying reasons for the large but

Differential action of glycoprotein hormones: significance in cancer progression.

PubMed

Govindaraj, Vijayakumar; Arya, Swathy V; Rao, A J

2014-02-01

Growth of multicellular organisms depends on maintenance of proper balance between proliferation and differentiation. Any disturbance in this balance in animal cells can lead to cancer. Experimental evidence is provided to conclude with special reference to the action of follicle-stimulating hormone (FSH) on Sertoli cells, and luteinizing hormone (LH) on Leydig cells that these hormones exert a differential action on their target cells, i.e., stimulate proliferation when the cells are in an undifferentiated state which is the situation with cancer cells and promote only functional parameters when the cell are fully differentiated. Hormones and growth factors play a key role in cell proliferation, differentiation, and apoptosis. There is a growing body of evidence that various tumors express some hormones at high levels as well as their cognate receptors indicating the possibility of a role in progression of cancer. Hormones such as LH, FSH, and thyroid-stimulating hormone have been reported to stimulate cell proliferation and act as tumor promoter in a variety of hormone-dependent cancers including gonads, lung, thyroid, uterus, breast, prostate, etc. This review summarizes evidence to conclude that these hormones are produced by some cancer tissues to promote their own growth. Also an attempt is made to explain the significance of the differential action of hormones in progression of cancer with special reference to prostate cancer.

[Plastic surgery for the treatment of gynaecomastia following hormone therapy in prostate carcinoma].

PubMed

Ryssel, H; Germann, G; Köllensperger, E; Riedel, K

2008-04-01

Gynecomastia is a potential side effect of hormone therapy for prostate cancer. In large, randomized, placebo controlled studies approximately 50% or more of patients with prostate cancer experienced gynecomastia attributable to various mechanisms. Although it is mostly reported as mild to moderate, gynecomastia is one of the reasons most frequently cited for premature discontinuation of such treatment. Prophylactic radiotherapy and prophylactic tamoxifen have been shown to decrease the incidence of hormone-induced gynecomastia; nevertheless, there are still cases of refractory gynecomastia, and in these plastic surgery is needed for correction. Gynecomastia is a benign enlargement of the male breast, requiring no treatment unless it is a source of embarrassment and/or distress for the adolescent or man affected. The indications for surgical treatment of gynecomastia are founded on two main objectives: restoration of the male chest shape and diagnostic evaluation of suspected breast lesions. The authors believe that the complete circumareolar technique with no further scarring creates the best aesthetic results with fewer complications. When this is used in combination with liposuction very pleasing aesthetic results can be achieved.

SYSTEMS MODELING OF PROSTATE REGULATION AND ...

EPA Pesticide Factsheets

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens. A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testost

Modulation of Androgen Receptor Signaling in Hormonal Therapy-Resistant Prostate Cancer Cell Lines

PubMed Central

Marques, Rute B.; Dits, Natasja F.; Erkens-Schulze, Sigrun; van IJcken, Wilfred F. J.; van Weerden, Wytske M.; Jenster, Guido

2011-01-01

Background Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. Methodology/Principal Findings Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa. Conclusions/Significance AR modifications altered the transcriptional response to (anti)androgens in

First Brazilian Consensus of Advanced Prostate Cancer: Recommendations for Clinical Practice.

PubMed

Sasse, Andre Deeke; Wiermann, Evanius Garcia; Herchenhorn, Daniel; Bastos, Diogo Assed; Schutz, Fabio A; Maluf, Fernando Cotait; Coura, George; Morbeck, Igor Alexandre Protzner; Cerci, Juliano J; Smaletz, Oren; Lima, Volney Soares; Adamy, Ari; Campos, Franz Santos de; Carvalhal, Gustavo Franco; Cezar, Leandro Casemiro; Dall'Oglio, Marcos Francisco; Sadi, Marcus Vinicius; Reis, Rodolfo Borges Dos; Nogueira, Lucas

2017-01-01

Prostate cancer still represents a major cause of morbidity, and still about 20% of men with the disease are diagnosed or will progress to the advanced stage without the possibility of curative treatment. Despite the recent advances in scientific and technological knowledge and the availability of new therapies, there is still considerable heterogeneity in the therapeutic approaches for metastatic prostate cancer. This article presents a summary of the I Brazilian Consensus on Advanced Prostate Cancer, conducted by the Brazilian Society of Urology and Brazilian Society of Clinical Oncology. Experts were selected by the medical societies involved. Forty issues regarding controversial issues in advanced disease were previously elaborated. The panel met for consensus, with a threshold established for 2/3 of the participants. The treatment of advanced prostate cancer is complex, due to the existence of a large number of therapies, with different response profiles and toxicities. The panel addressed recommendations on preferred choice of therapies, indicators that would justify their change, and indicated some strategies for better sequencing of treatment in order to maximize the potential for disease control with the available therapeutic arsenal. The lack of consensus on some topics clearly indicates the absence of strong evidence for some decisions. Copyright® by the International Brazilian Journal of Urology.

Familial isolated growth-hormone deficiency with advanced sexual maturation.

PubMed

Kauschansky, A; Cohen, H A; Varsano, I; Laron, Z; Frydman, M

1993-02-01

Two brothers, aged 15 1/2 and 13 1/2 years, with dwarfism, microcephaly, and advanced sexual and skeletal maturation are described. One patient was mentally retarded. The parents were first cousins. Endocrine studies of these patients documented low growth-hormone levels after clonidine and insulin stimulation and blunted growth-hormone response to growth hormone releasing hormone. Gonadotropin releasing hormone stimulation produced no changes in levels of luteinizing and follicle-stimulating hormones. Basal levels of 17-alpha-hydroxyprogesterone were elevated in the two patients and increased further in response to stimulation with corticotropin. Levels of testosterone, dehydroepiandrosterone sulfate, and androstenedione were variably increased in both patients and showed a proportional increase on stimulation with human chorionic gonadotropin. To our knowledge, this is the first report of a familial association between growth-hormone deficiency and advanced bone and sexual maturation. A pituitary and an independent adrenal defect could account for the observations in these patients, but in view of the familial recurrence, a common underlying defect is possible.

Advances in prostate-specific membrane antigen PET of prostate cancer.

PubMed

Bouchelouche, Kirsten; Choyke, Peter L

2018-05-01

In recent years, a large number of reports have been published on prostate-specific membrane antigen (PSMA)/PET in prostate cancer (PCa). This review highlights advances in PSMA PET in PCa during the past year. PSMA PET/computed tomography (CT) is useful in detection of biochemical recurrence, especially at low prostate-specific antigen (PSA) values. The detection rate of PSMA PET is influenced by PSA level. For primary PCa, PSMA PET/CT shows promise for tumour localization in the prostate, especially in combination with multiparametric MRI (mpMRI). For primary staging, PSMA PET/CT can be used in intermediate and high-risk PCa. Intraoperative PSMA radioligand guidance seems promising for detection of malignant lymph nodes. While the use of PSMA PET/MRI in primary localized disease is limited to high and intermediate-risk patients and localized staging, in the recurrence setting, PET/MRI can be particularly helpful when the lesions are subtle. PSMA PET/CT is superior to choline PET/CT and other conventional imaging modalities. Molecular imaging with PSMA PET continues to pave the way for personalized medicine in PCa.However, large prospective clinical studies are still needed to fully evaluate the role of PSMA PET/CT and PET/MRI in the clinical workflow of PCa.

Characterization of neuroendocrine differentiation in human benign prostate and prostatic adenocarcinoma.

PubMed

Aprikian, A G; Cordon-Cardo, C; Fair, W R; Reuter, V E

1993-06-15

This report describes an immunohistopathologic analysis characterizing the incidence, pattern of distribution, and hormonal content of neuroendocrine (NE) cells in human benign prostate and prostatic adenocarcinoma. Formaldehyde-fixed, paraffin-embedded material from 15 benign prostates, 31 primary prostatic adenocarcinomas, 16 metastatic lesions, 21 primary tumors treated with short-course diethylstilbestrol (DES), and 10 specimens from hormone-refractory patients were examined. NE cells were identified using silver histochemistry and a panel of immunohistochemical NE markers (chromogranin-A, serotonin, neuron-specific enolase), and specific peptide hormone antibodies. NE cells were identified in all benign prostates. NE cells were identified in 77% of primary untreated adenocarcinomas with no significant differences with respect to pathologic stage. NE cells were found isolated and dispersed in the tumor, composing the minority of malignant cells. Double-labeling and serial section immunohistochemistry demonstrated the coexpression of prostate-specific antigen (PSA) in NE cells. In addition to serotonin, some tumors expressed multiple hormone immunoreactivities. NE cells were identified in 56% of metastatic deposits, with a similar pattern of distribution. In DES-treated cases, NE cells were found consistently in the adjacent benign epithelium, whereas 52% of tumors contained NE cells. Hormone-refractory tumors contained NE cells in 60% of cases. This analysis demonstrates that a significant proportion of primary and metastatic prostatic adenocarcinomas contain a subpopulation of NE cells, the expression of which does not appear to be suppressed with androgen ablation and does not correlate with pathologic stage. Furthermore, NE cells coexpress PSA, suggesting a common precursor cell of origin. The elaboration of biogenic amines and neuropeptides suggests that NE cells dispersed in prostatic carcinoma may play a paracrine growth-regulatory role.

The role of serum osteoprotegerine in metastatic prostate cancer - a case control study.

PubMed

Siampanopoulou, M; El, Mantani; Moustakas, G; Haritanti, A; Gotzamani-Psarrakou, A

2016-01-01

Prostate cancer is one of the most common malignant neoplastic diseases in men. Early control of the disease progression contributes significantly to survival rates and patients' quality of life. Osteoprotegerin is a dimeric glycoprotein, which affects bone metabolism and inhibits osteoclastogenesis. In the present study, we evaluated the expression of osteoprotegerin in the serum of prostate cancer patients with or without skeletal metastases. The expression of serum osteoprotegerin, as measured by enzyme-linked immunosorbent assay, has been studied in 82 patients with locally controlled prostate cancer, in 49 patients with metastatic bone disease and in a control group of 41 healthy males. At sampling time 65/131 of included patients were newly diagnosed, while 66/131 patients were already under hormonal therapy. All eligible prostate cancer patients had histologically confirmed malignancy. Serum total prostate-specific antigen (PSA) was determined by an immunoradiometric assay. We investigated the expression of osteoprotegerin in hormone-dependent and hormone-refractory prostate cancer and its relation to disease progression. Among the 131 patients with prostate cancer, higher osteoprotegerin and PSA concentrations have been observed in metastatic bone patients' sera (p <0.001). ROC analysis between the metastatic and locally controlled prostate cancer patients has shown a statistically significant area curve (p <0.001) and a cut-off limit of 89.6 pg/ml. Moreover, 15.3 % of patients became hormone-resistant, with osteoprotegerin values significantly increased compared with hormone-sensitive prostate cancer patients (p <0.001). It seems that elevated levels of serum osteoprotegerin in patients with prostate cancer reflect the bone metastatic extent and may potentially be used in metastatic patients' follow-ups. Hippokratia 2016, 20(2): 133-138.

Advances in male hormonal contraception.

PubMed

Costantino, Antonietta; Gava, Giulia; Berra, Marta; Meriggiola Maria, Cristina

2014-11-01

Contraception is a basic human right for its role on health, quality of life and wellbeing of the woman and of the society as a whole. Since the introduction of female hormonal contraception the responsibility of family planning has always been with women. Currently there are only a few contraceptive methods available for men, but recently, men have become more interested in supporting their partners actively. Over the last few decades different trials have been performed providing important advances in the development of a safe and effective hormonal contraceptive for men. This paper summarizes some of the most recent trials.

Growth hormone-releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan-induced chronic prostatitis.

PubMed

Popovics, Petra; Cai, Renzhi; Sha, Wei; Rick, Ferenc G; Schally, Andrew V

2018-05-21

Inflammation plays a key role in the etiology of benign prostatic hyperplasia (BPH) through multiple pathways involving the stimulation of proliferation by cytokines and growth factors as well as the induction of the focal occurrence of epithelial-to-mesenchymal transition (EMT). We have previously reported that GHRH acts as a prostatic growth factor in experimental BPH and in autoimmune prostatitis models and its blockade with GHRH antagonists offer therapeutic approaches for these conditions. Our current study was aimed at the investigation of the beneficial effects of GHRH antagonists in λ-carrageenan-induced chronic prostatitis and at probing the downstream molecular pathways that are implicated in GHRH signaling. To demonstrate the complications triggered by recurrent/chronic prostatic inflammation in Sprague-Dawley rats, 50 μL 3% carrageenan was injected into both ventral prostate lobes two times, 3 weeks apart. GHRH antagonist, MIA-690, was administered 5 days after the second intraprostatic injection at 20 μg daily dose for 4 weeks. GHRH-induced signaling events were identified in BPH-1 and in primary prostate epithelial (PrEp) cells at 5, 15, 30, and 60 min with Western blot. Inflammation induced prostatic enlargement and increased the area of the stromal compartment whereas treatment with the GHRH antagonist significantly reduced these effects. This beneficial activity was consistent with a decrease in prostatic GHRH, inflammatory marker COX-2, growth factor IGF-1 and inflammatory and EMT marker TGF-β1 protein levels and the expression of multiple genes related to EMT. In vitro, GHRH stimulated multiple pathways involved in inflammation and growth in both BPH-1 and PrEp cells including NFκB p65, AKT, ERK1/2, EGFR, STAT3 and increased the levels of TGF-β1 and Snail/Slug. Most interestingly, GHRH also stimulated the transactivation of the IGF receptor. The study demonstrates that GHRH antagonists could be beneficial for the treatment of

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

PubMed

Mangini, Neha S; Wesolowski, Robert; Ramaswamy, Bhuvaneswari; Lustberg, Maryam B; Berger, Michael J

2015-11-01

To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer. © The Author(s) 2015.

Time-dependent change of blood flow in the prostate treated with high-intensity focused ultrasound.

PubMed

Shoji, Sunao; Tonooka, Akiko; Hashimoto, Akio; Nakamoto, Masahiko; Tomonaga, Tetsuro; Nakano, Mayura; Sato, Haruhiro; Terachi, Toshiro; Koike, Junki; Uchida, Toyoaki

2014-09-01

Avascular areas on contrast-enhanced magnetic resonance imaging have been considered to be areas of localized prostate cancer successfully treated by high-intensity focused ultrasound. However, the optimal timing of magnetic resonance imaging has not been discussed. The thermal effect of high-intensity focused ultrasound is degraded by regional prostatic blood flow. Conversely, the mechanical effect of high-intensity focused ultrasound (cavitation) is not affected by blood flow, and can induce vessel damage. In this series, the longitudinal change of blood flow on contrast-enhanced magnetic resonance imaging was observed from postoperative day 1 to postoperative day 14 in 10 patients treated with high-intensity focused ultrasound. The median rates of increase in the non-enhanced volume of the whole gland, transition zone and peripheral zone from postoperative day 1 to postoperative day 14 were 36%, 39%, and 34%, respectively. In another pathological analysis of the prostate tissue of 17 patients immediately after high-intensity focused ultrasound without neoadjuvant hormonal therapy, we observed diffuse coagulative degeneration and partial non-coagulative prostate tissue around arteries with vascular endothelial cell detachment. These observations on contrast-enhanced magnetic resonance imaging support a time-dependent change of the blood flow in the prostate treated with high-intensity focused ultrasound. Additionally, our pathological findings support the longitudinal changes of these magnetic resonance imaging findings. Further large-scale studies will investigate the most appropriate timing of contrast-enhanced magnetic resonance imaging for evaluation of the effectiveness of high-intensity focused ultrasound for localized prostate cancer. © 2014 The Japanese Urological Association.

Molecular pathways and targets in prostate cancer

PubMed Central

Shtivelman, Emma; Beer, Tomasz M.; Evans, Christopher P.

2014-01-01

Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease. The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors. It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways. Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies. The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer. This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge. PMID:25277175

Advancements in MR Imaging of the Prostate: From Diagnosis to Interventions

PubMed Central

Bonekamp, David; Jacobs, Michael A.; El-Khouli, Riham; Stoianovici, Dan

2011-01-01

Prostate cancer is the most frequently diagnosed cancer in males and the second leading cause of cancer-related death in men. Assessment of prostate cancer can be divided into detection, localization, and staging; accurate assessment is a prerequisite for optimal clinical management and therapy selection. Magnetic resonance (MR) imaging has been shown to be of particular help in localization and staging of prostate cancer. Traditional prostate MR imaging has been based on morphologic imaging with standard T1-weighted and T2-weighted sequences, which has limited accuracy. Recent advances include additional functional and physiologic MR imaging techniques (diffusion-weighted imaging, MR spectroscopy, and perfusion imaging), which allow extension of the obtainable information beyond anatomic assessment. Multiparametric MR imaging provides the highest accuracy in diagnosis and staging of prostate cancer. In addition, improvements in MR imaging hardware and software (3-T vs 1.5-T imaging) continue to improve spatial and temporal resolution and the signal-to-noise ratio of MR imaging examinations. Another recent advancement in the field is MR imaging guidance for targeted prostate biopsy, which is an alternative to the current standard of transrectal ultrasonography–guided systematic biopsy. © RSNA, 2011 PMID:21571651

[Rational imaging in locally advanced prostate cancer].

PubMed

Beissert, M; Lorenz, R; Gerharz, E W

2008-11-01

Prostate cancer is one of the principal medical problems facing the male population in developed countries with an increasing need for sophisticated imaging techniques and risk-adapted treatment options. This article presents an overview of the current imaging procedures in the diagnosis of locally advanced prostate cancer. Apart from conventional gray-scale transrectal ultrasound (TRUS) as the most frequently used primary imaging modality we describe computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). CT and MRI not only allow assessment of prostate anatomy but also a specific evaluation of the pelvic region. Color-coded and contrast-enhanced ultrasound, real-time elastography, dynamic contrast enhancement in MR imaging, diffusion imaging, and MR spectroscopy may lead to a clinically relevant improvement in the diagnosis of prostate cancer. While bone scintigraphy with (99m)Tc-bisphosphonates is still the method of choice in the evaluation of bone metastasis, whole-body MRI and PET using (18)F-NaF, (18)F-FDG, (11)C-choline, (11)C-acetate, and (18)F-choline as tracers achieve higher sensitivities.

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

PubMed

Chen, RuiQi; Yu, Yue; Dong, Xuesen

2017-02-01

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. Copyright © 2016 Elsevier Ltd. All rights reserved.

Locally Advanced Prostate Cancer: Three-Dimensional Magnetic Resonance Spectroscopy to Monitor Prostate Response to Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valentini, Anna Lia, E-mail: alvalentini@rm.unicatt.it; Gui, Benedetta; D'Agostino, Giuseppe Roberto

2012-11-01

Purpose: To correlate results of three-dimensional magnetic resonance spectroscopic imaging (MRSI) with prostate-specific antigen (PSA) levels and time since external beam irradiation (EBRT) in patients treated with long-term hormone therapy (HT) and EBRT for locally advanced disease to verify successful treatment by documenting the achievement of metabolic atrophy (MA). Methods and Materials: Between 2006 and 2008, 109 patients were consecutively enrolled. MA was assessed by choline and citrate peak area-to-noise-ratio <5:1. Cancerous metabolism (CM) was defined by choline-to-creatine ratio >1.5:1 or choline signal-to-noise-ratio >5:1. To test the strength of association between MRSI results and the time elapsed since EBRT (TEFRT),more » PSA levels, Gleason score (GS), and stage, logistic regression (LR) was performed. p value <0.05 was statistically significant. The patients' outcomes were verified in 2011. Results: MRSI documented MA in 84 of 109 and CM in 25 of 109 cases. LR showed that age, GS, stage, and initial and recent PSA had no significant impact on MRSI results which were significantly related to PSA values at the time of MRSI and to TEFRT. Patients were divided into three groups according to TEFRT: <1 year, 1-2 years, and >2 years. MA was detected in 54.1% of patients of group 1, 88.9% of group 2, and in 94.5% of group 3 (100% when PSA nadir was reached). CM was detected in 50% of patients with reached PSA nadir in group 1. Local relapse was found in 3 patients previously showing CM at long TEFRT. Conclusion: MA detection, indicative of successful treatment because growth of normal or abnormal cells cannot occur without metabolism, increases with decreasing PSA levels and increasing time on HT after EBRT. This supports long-term HT in advanced prostate cancer. Larger study series are needed to assess whether MRSI could predict local relapse by detecting CM at long TEFRT.« less

Akt Inhibitor MK2206 and Hydroxychloroquine in Treating Patients With Advanced Solid Tumors, Melanoma, Prostate or Kidney Cancer

ClinicalTrials.gov

2018-05-15

Adult Solid Neoplasm; Hormone-Resistant Prostate Carcinoma; Recurrent Melanoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Prostate Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7

Use of advanced treatment technologies among men at low risk of dying from prostate cancer.

PubMed

Jacobs, Bruce L; Zhang, Yun; Schroeck, Florian R; Skolarus, Ted A; Wei, John T; Montie, James E; Gilbert, Scott M; Strope, Seth A; Dunn, Rodney L; Miller, David C; Hollenbeck, Brent K

2013-06-26

The use of advanced treatment technologies (ie, intensity-modulated radiotherapy [IMRT] and robotic prostatectomy) for prostate cancer is increasing. The extent to which these advanced treatment technologies have disseminated among patients at low risk of dying from prostate cancer is uncertain. To assess the use of advanced treatment technologies, compared with prior standards (ie, traditional external beam radiation treatment [EBRT] and open radical prostatectomy) and observation, among men with a low risk of dying from prostate cancer. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified a retrospective cohort of men diagnosed with prostate cancer between 2004 and 2009 who underwent IMRT (n = 23,633), EBRT (n = 3926), robotic prostatectomy (n = 5881), open radical prostatectomy (n = 6123), or observation (n = 16,384). Follow-up data were available through December 31, 2010. The use of advanced treatment technologies among men unlikely to die from prostate cancer, as assessed by low-risk disease (clinical stage ≤T2a, biopsy Gleason score ≤6, and prostate-specific antigen level ≤10 ng/mL), high risk of noncancer mortality (based on the predicted probability of death within 10 years in the absence of a cancer diagnosis), or both. In our cohort, the use of advanced treatment technologies increased from 32% (95% CI, 30%-33%) to 44% (95% CI, 43%-46%) among men with low-risk disease (P < .001) and from 36% (95% CI, 35%-38%) to 57% (95% CI, 55%-59%) among men with high risk of noncancer mortality (P < .001). The use of these advanced treatment technologies among men with both low-risk disease and high risk of noncancer mortality increased from 25% (95% CI, 23%-28%) to 34% (95% CI, 31%-37%) (P < .001). Among all patients diagnosed in SEER, the use of advanced treatment technologies for men unlikely to die from prostate cancer increased from 13% (95% CI, 12%-14%), or 129.2 per 1000 patients diagnosed with prostate cancer, to 24% (95

Radical Prostatectomy for Locally Advanced Prostate Cancers-Review of Literature.

PubMed

Srivatsa, N; Nagaraja, H; Shweta, S; Raghunath, S K

2017-06-01

Twenty-five to thirty percent of patients with prostate cancer present with locally advanced disease. While risk stratification remains the same with high incidence of upstaging of disease on imaging and histopathological evaluation; there have been progressive refinements in surgical therapy. With availability of reasonably robust data, radical prostatectomy in men with locally advanced prostate cancers seems to effect improvement in both cancer specific and overall survival rates in comparison to the current standard of care of radiation with androgen deprivation therapy. Studies using radical prostatectomy as a part of multimodality approach have also shown promising results. There is an imminent need for well-designed prospective studies of benefits of radical prostatectomy over radiation and androgen deprivation as well as benefits of multimodality therapy over monotherapy. Surgery for patients with locally advanced prostate cancer is technically challenging. Surgical outcomes are comparable to those of organ-confined disease when performed in high-volume centers. Neoadjuvant therapies prior to radical prostatectomy might improve surgical outcomes, but whether they will translate into a better cancer specific and overall survival are yet to be ascertained.

Old issues and new perspectives on prostate cancer hormonal therapy: the molecular substratum.

PubMed

Reis, Leonardo Oliveira

2012-09-01

Secondary hormonal therapy is a treatment option in patients with castration-resistant prostate cancer (CRPC); however, it is underutilized and is room for optimization and improvement. In this context, androgen receptor (AR) is the Achilles' heel, being critically important and various mechanisms ranging from receptor mutations to secondary signaling pathways are responsible for some of the biological heterogeneity, demanding a multimodal approach. A comprehensive review of the peer-reviewed literature is performed on the topic of molecular mechanisms supporting secondary hormonal therapies, including expanded alternative hormonal therapies for CRPC. Essential concepts in clinical treatment of patients with progression on primary hormonal therapy are maintaining the castrate state, accounting for the intermittency phenomenon and sequentially using oral antiandrogens and adrenolytics heading to androgen depletion microenvironment. Survival prolongation, pain relief or measurable improvement in tumor-related symptoms should be persecuted and are considered to be a tangible benefit of obvious worth to the patient. Understanding the underlying molecular substratum is of paramount importance to hormonal therapy optimization in this context once current androgen-depletion strategies are incomplete, and residual androgens as well as alternative routes contribute to sustained AR activity and disease progression to a lethal phenotype. One or many mechanisms may be playing a role, even within the same patient and lastly are potential targets for treatment. Five fundamental mechanisms mediated through the AR to promote tumor growth (three of which depend on ligand signaling) added to the stem cell pathway must be recognized in CRPC. They are persistence of intratumoral androgens as a result of in situ steroidogenesis or adrenal source; AR mutations that allow promiscuous activation by otherwise nonsignaling ligands; wild-type AR gene amplification; alterations in AR

Apoptosis-Dependent and Apoptosis-Independent Functions Bim in Prostate Cancer Cells

DTIC Science & Technology

2004-03-01

AD_ Award Number: DAMD17-03-1-0146 TITLE: Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL...FUNDING NUMBERS Apoptosis-Dependent and Apoptosis-Independent Functions of DAMD17-03-1-0146 Bim in Prostate Cancer Cells 6. A UTHORs) Junwei Liu, M.D...extended cell survival have been implicated in prostate cancer (PCa) development and progression. We recently found that Bim , a BH3-only pro

Prospective trial of an herbal formula BYSH and Saw palmetto in patients with hormonal refractory prostate cancer: a pilot study.

PubMed

Ng, Anthony C-F; Cheng, K-F; Leung, P-C

2014-01-01

BYSH, a herbal formula, was evaluated for efficacy and safety in a pilot study for patients with advanced hormone refractory prostate cancer (HRPC). The pilot study was designed as a single-center open-label trial. Patients with HRPC were treated with BYSH for 24 weeks. The primary end point was the changes in serum prostate-specific antigen (PSA) level. Safety parameters such as liver and renal functions were monitored during the study period. Ten patients were eligible for the study. Most of them had stable PSA levels while taking BYSH. However, at the end of the BYSH treatment, the level of PSA increased. The median survival from diagnosis of HRPC was 16.4 months. Liver and renal functions remained normal. BYSH was well tolerated and no patient reported adverse events during the study period. Although it is inappropriate to make a conclusion based on the pilot study results, the trend of improvement is obvious. Further investigations should be conducted to demonstrate its clinical benefits. We have also briefly reviewed some plant products which are patented and also available in market.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial

PubMed Central

Mason, Malcolm D.; Clarke, Noel W.; James, Nicholas D.; Dearnaley, David P.; Spears, Melissa R.; Ritchie, Alastair W.S.; Attard, Gerhardt; Cross, William; Jones, Rob J.; Parker, Christopher C.; Russell, J. Martin; Thalmann, George N.; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A.; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D.; O’Sullivan, Joe M.; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K.B.; Sydes, Matthew R.

2017-01-01

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.

PubMed

Mason, Malcolm D; Clarke, Noel W; James, Nicholas D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Attard, Gerhardt; Cross, William; Jones, Rob J; Parker, Christopher C; Russell, J Martin; Thalmann, George N; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D; O'Sullivan, Joe M; Porfiri, Emilio; Protheroe, Andrew; Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K B; Sydes, Matthew R

2017-05-10

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned

Split-course, high-dose palliative pelvic radiotherapy for locally progressive hormone-refractory prostate cancer.

PubMed

Gogna, Nirdosh Kumar; Baxi, Siddhartha; Hickey, Brigid; Baumann, Kathryn; Burmeister, Elizabeth; Holt, Tanya

2012-06-01

Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients. A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45-60 Gy in 18-24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity. The median age was 71 years (range, 53-88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported. The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported. Copyright © 2012 Elsevier Inc. All rights reserved.

[Prostate cancer. Epidemiology. Risk factors. Pathology].

PubMed

Fournier, G; Valeri, A; Mangin, P; Cussenot, O

2004-10-01

Prostate cancer (prostate adenocarcinoma) has become an important concern in terms of public health these past fifteen years; recent French epidemiological data revealed 10,104 deaths due to this disease in 2000. The two main factors involved are the serum prostatic specific antigen (PSA), routinely used since late 1980's and which allows early diagnosis (before symptom onset), and the lengthened duration of life. Such cancer is rare before the age of 50, but its frequency increases with age, making it the most frequent type of cancer in French men. Although the aetiology of this disease is unknown, the ethnic origin, and a familial history of prostate or breast cancer are known risk factors. Predisposing genes to such hereditary types remain to be identified. Other genetic factors (polymorphisms), combined with environmental factors such as nutrition, have been incriminated, which is likely to explain the geographical variations of this affection. At the molecular level, the mechanisms involved in the tumoral initiation and progression remain unclear. Various genetic alterations have been identified among the genome of cancerous cells, at various stages of the affection: intraepithelial neoplasia, localized, locally advanced, metastatic or hormone refractory stage -, hormonal escape). However, the precise sequence and nature of the complex molecular events remain to be determined prior to their routine utilisation in the determination of subjects at risk, or as prognostic factors, and even as therapeutic targets. The anatomopathology is a key for the diagnosis. Intraepithelial neoplasia is the pre-cancerous lesion observed in most adenocarcinomas; these are localized in the peripheral part of the prostate gland in 70% of the cases. Gleason's classification is the current gold standard for the determination of tumoral aggressiveness and categorisation of the adenocarcinomas which are basically heterogeneous (coexistence of tumors cells with different degrees of

Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

PubMed

Turner, Nicholas C; Ro, Jungsil; André, Fabrice; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Loibl, Sibylle; Huang Bartlett, Cynthia; Zhang, Ke; Giorgetti, Carla; Randolph, Sophia; Koehler, Maria; Cristofanilli, Massimo

2015-07-16

Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer. This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted

Development of Antibodies Against Novel Cell Surface Proteins In Hormone Refractory Prostate Cancer. Addendum

DTIC Science & Technology

2011-07-01

marker of hormone refractory metastatic prostate cancer. Clin Cancer Res, 2005. 15: 2237- 43 . 3. Tomita K, van Bokhoven A, van Leenders GJ, Ruijter...Santa Cruz Biotechnology), vimentin, Ki-67 (DakoCytomation) and caspase-3 (Cell Signaling Technology). Flow cytometry was performed with N...transduced cells were labeled with N-cadherin–specific antibody and sorted by flow cytometry , gating for a GFP-positive, N-cadherinlow population. The

Flow cytometric monitoring of hormone receptor expression in human solid tumors

NASA Astrophysics Data System (ADS)

Krishan, Awtar

2002-05-01

Hormone receptor expression in human breast and prostate tumors is of diagnostic and therapeutic importance. With the availability of anti-estrogen, androgen and progesterone antibodies, immunohistochemistry has become a standard tool for determination of receptor expression in human tumor biopsies. However, this method is dependent on examination of a small number of cells under a microscope and the data obtained in most cases is not quantitative. As most of the commercially used anti-hormone antibodies have nuclear specificity, we have developed methods for isolation and antigen unmasking of nuclei from formalin fixed/paraffin embedded archival human tumors. After immunostaining with the antibodies and propidium iodide (for DNA content and cell cycle analysis), nuclei are analyzed by multiparametric laser flow cytometry for hormone receptor expression, DNA content, aneuploidy and cell cycle determination. These multiparametric methods are especially important for retrospective studies seeking to correlate hormone receptor expression with clinical response to anti-hormonal therapy of human breast and prostate tumors.

Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.

PubMed

Pritchard, Colin C; Morrissey, Colm; Kumar, Akash; Zhang, Xiaotun; Smith, Christina; Coleman, Ilsa; Salipante, Stephen J; Milbank, Jennifer; Yu, Ming; Grady, William M; Tait, Jonathan F; Corey, Eva; Vessella, Robert L; Walsh, Tom; Shendure, Jay; Nelson, Peter S

2014-09-25

A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers.

[Treatment of localized prostate cancer].

PubMed

Vallancien, Guy; Cathelineau, Xavier; Rozet, François; Barret, Eric

2008-05-01

Treatments for localized prostate cancer include radical prostatectomy, brachytherapy, conformal external beam irradiation, and focused ultrasound. This paper describes the oncologic and functional results of each approach. The treatment choice depends on the patient's general status and on the results of biopsy and imaging studies. Watchful waiting and hormone therapy are other options for elderly patients.

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

PubMed Central

Blok, L J; Chang, G T G; Steenbeek-Slotboom, M; Weerden, W M van; Swarts, H G P; Pont, J J H H M De; Steenbrugge, G J van; Brinkmann, A O

1999-01-01

The β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the β1-subunit was initiated at concentrations between 0.01 nM and 0.03 nM of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of β1-subunit protein, but not of the α1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na+,K+-ATPase in the membrane (measured by 3H-ouabain binding) was also markedly decreased. The main function of Na+,K+-ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na+,K+-ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na+,K+-ATPase expression, did not result in significant protection against the chemotherapeutic agent. © 1999 Cancer Research Campaign PMID:10487609

Expression of Voltage-Gated Sodium Channel Nav1.8 in Human Prostate Cancer is Associated with High Histological Grade

PubMed Central

Suy, Simeng; Hansen, Todd P.; Auto, Heather D.; Kallakury, Bhaskar V.S.; Dailey, Vernon; Danner, Malika; MacArthur, Linda; Zhang, Ying; Miessau, Matthew J.; Collins, Sean P.; Brown, Milton L.

2013-01-01

Voltage-gated sodium (Nav) channels are required for impulse conductance in excitable tissues. Navs have been linked to human cancers, including prostate. The expression and distribution of Nav isoforms (Nav1.1-Nav1.9) in human prostate cancer are not well established. Here, we evaluated the expression of these isoforms and investigated the expression of Nav1.8 in human prostate cancer tissues. Nav1.8 was highly expressed in all examined cells. Expression of Nav1.1, Nav1.2, and Nav1.9 were high in DU-145, PC-3 and PC-3M cells compared to LNCaP (hormone-dependent), C4-2, C4-2B, and CWR22Rv-1 cells. Nav1.5 and Nav1.6 were expressed in all cells examined. Nav1.7 expression was absent in PC-3M and CWR22Rv-1, but expressed in the other cells examined. Immunohistochemistry revealed intensive Nav1.8 staining correlated with more advanced pathologic stage of disease. Increased intensity of nuclear Nav1.8 correlated with increased Gleason grade. Our results revealed that Nav1.8 is universally expressed in human prostate cancer cells. Nav1.8 expression statistically correlated with pathologic stage (P=0.04) and Gleason score (P=0.01) of human prostate tissue specimens. The aberrant nuclear localization of Nav1.8 with advanced prostate cancer tissues warrant further investigation into use of Nav1.8 as a potential biomarker to differentiate between early and advanced disease. PMID:24163825

Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tian Junqiang; Ning Shouchen; Knox, Susan J., E-mail: sknox@stanford.ed

Purpose: We have previously shown that sodium selenite (SSE) increases radiation-induced cell killing of human prostate carcinoma cells in vitro. In this study we further evaluated the in vivo radiosensitizing effect of SSE in prostate cancer xenograft tumors and normal radiosensitive intestinal crypt cells. Methods and Materials: Immunodeficient (SCID) mice with hormone-independent LAPC-4 (HI-LAPC-4) and PC-3 xenograft tumors (approximately 200 mm{sup 3}) were divided into four groups: control (untreated), radiation therapy (XRT, local irradiation), SSE (2 mg/kg, intraperitoneally, 3 times/week), and XRT plus SSE. The XRT was given at the beginning of the regimen as a single dose of 5more » Gy for HI-LAPC-4 tumors and a single dose of 7 Gy followed by a fractional dose of 3 Gy/d for 5 days for PC-3 tumors. The tumor volume was measured 3 times per week. The radiosensitizing effect of SSE on normal intestinal epithelial cells was assessed by use of a crypt cell microcolony assay. Results: In the efficacy study, SSE alone significantly inhibited the tumor growth in HI-LAPC-4 tumors but not PC-3 tumors. Sodium selenite significantly enhanced the XRT-induced tumor growth inhibition in both HI-LAPC-4 and PC-3 tumors. In the toxicity study, SSE did not affect the intestinal crypt cell survival either alone or in combination with XRT. Conclusions: Sodium selenite significantly enhances the effect of radiation on well-established hormone-independent prostate tumors and does not sensitize the intestinal epithelial cells to radiation. These results suggest that SSE may increase the therapeutic index of XRT for the treatment of prostate cancer.« less

Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

PubMed

Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

2018-06-01

Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

Sexual healing in patients with prostate cancer on hormone therapy.

PubMed

Schover, Leslie R

2015-01-01

Since prostate cancer becomes more common with age, at least one-third of men have sexual problems at diagnosis. All localized treatments for prostate cancer greatly increase the prevalence of sexual dysfunction, which include loss of desire, erectile dysfunction, and changes in orgasm. Even men on active surveillance have a higher rate of problems than matched peers without prostate cancer. However, men given androgen deprivation therapy (ADT) have the worst rates of sexual dysfunction. Even after 3 to 4 months of ADT, men's desire for sex is decreased and irreversible damage may occur to the erectile tissue in the penis. Erections do not recover in about one-half of men, even if ADT is discontinued. Although intermittent ADT allows some recovery of sexual function, serum testosterone requires 9 to 12 months off ADT to recover. Again, one-half of men have permanent erectile dysfunction. If ADT causes atrophy of the erectile tissue, blood leaks out of the venous system during erection. This syndrome is difficult to treat except with surgery to implant a penile prosthesis. Despite the high rate of sexual problems in men on ADT, a small group stays sexually active and is able to have reliable erections. To improve men's sexual satisfaction on ADT, it may be important to educate them about getting extra mental and physical sexual stimulation, as well as using penile rehabilitation during hormone therapy. Information on reaching orgasm and coping with problems such as dry orgasm, pain with orgasm, and urinary incontinence during sex also should be provided.

The transcriptional programme of the androgen receptor (AR) in prostate cancer.

PubMed

Lamb, Alastair D; Massie, Charlie E; Neal, David E

2014-03-01

The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin-immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors. © 2013 The Authors. BJU International © 2013 BJU International.

[A case of locally advanced prostate cancer with low serum testosterone associated with intake of an androgenic medicine].

PubMed

Sakura, Mizuaki; Tsukamoto, Tetsurou; Yonese, Junji; Nakaishi, Masayuki; Maezawa, Takuya; Takimoto, Keita; Fukui, Iwao

2003-05-01

A 74-year-old man was referred to our clinic for the work-up of digitally hard and irregularly surfaced prostate and elevated serum prostate-specific antigen (PSA). His serum PSA was elevated to 41 ng/ml, but testosterone and LH level were decreased to 23.5 ng/dl and 0.5 mIU/ml, respectively. He had a history of taking an androgenic medicine containing methyl-testosterone 2 to 3 times a week for 2 year and 6 months. Transrectal sextant prostatic biopsy revealed moderately differentiated adenocarcinoma (Gleason score: 3 + 4) in 6 of 6 specimens and CT scan of the abdomen showed an enlarged obturator lymph-node (15 mm), resulting in the diagnosis of stage D1 (T3aN1M0) prostate cancer. Since serum testosterone level seemed to recover around the normal level after discontinuation of the exogenous androgen, we treated him with combination androgen blockade with LHRH agonist and bicaltamide, although his testosterone level was very low. Indeed, serum PSA decreased to 0.09 ng/ml and the right obturator node was markedly reduced by the hormone treatment. After the neoadjuvant therapy of 6 months duration, radical prostatectomy and limited pelvic lymph node dissection was carried out. Histologically, viable cancer cells were not found in any of resected lymph nodes, but they remained in bilateral lobes of the prostate (pT2bN0). The histological effect of the neoadjuvant hormone therapy according to General rule for Clinical and Pathological Studies on Prostate Cancer (3rd ed.) was grade 2. The patient has been well with undetectable PSA and no evidence of clinical failure for more than 12 months, though serum testosterone level recovered to near normal (288 ng/dl) 8 months after the cessation of the hormone treatment following the operation. Combination androgen blockade or non-steroidal anti-androgen agent appears to be effective for the treatment of prostatic cancer patients who takes exogenous androgenic medicine, even with a suppressed low serum testosterone level.

Triptorelin embonate: a 6-month formulation for prostate cancer.

PubMed

Whelan, Peter

2010-12-01

Luteinizing hormone releasing hormone (LH RH) agonists are the major agent for androgen deprivation therapy in advanced and metastatic prostate cancer. They also have a role in endometriosis, uterine fibroids and central precocious puberty. Triptorelin embonate 22.5 mg is a new, sustained-release, 6-month formulation of an LH RH agonist. It possesses longer duration of action than the current standard 3-month preparation and appears to have similar efficacy and side effects. The use of LH RH agonists for androgen deprivation in prostate cancer has increased considerably in the last 20 years. Recent work has shown that some of this usage has constituted overtreatment and it is within these newer paradigms of therapy that the new 6-month preparation is situated. The new 6-month LH RH preparation - triptorelin embonate - will be of help in several key areas of therapy for prostate cancer, notably as an adjunct to radiation therapy and chemotherapy. It possesses a similar effect, but with fewer side effects, than those that are now commonly available.

Cabazitaxel for the treatment of prostate cancer.

PubMed

Michielsen, Dirk P J; Braeckman, Johan G; Denis, Louis

2011-04-01

Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal suppression. Despite the castrate levels of testosterone, with time, prostate cancer gradually evolves into a castration-refractory state. Chemotherapeutic agents are able to influence the natural history of metastatic castration-resistant prostate cancer. Docetaxel is a clinically relevant, FDA-approved taxane. Today, it is the first-line chemotherapeutic agent in castration-refractory prostate cancer (CRPC). There is no standard second-line chemotherapeutic regimen. This review provides information on the efficacy of cabazitaxel as a second-line treatment for CRPC. The medline database was searched for clinical trials on chemotherapeutical treatment options of castration-resistant prostate cancer. All available data on the efficacy of cabazitaxel are summarized. New treatment strategies for castration-resistant prostate cancer should primarily focus on quality of life. In this view, vaccination therapy seems promising because of the acceptable level of toxicity. However, more research is needed to prove their efficacy in the treatment of castration-resistant prostate cancer. Cabazitaxel seems to be a promising second-line therapy in CRPC.

Anti-tumour activity of platinum compounds in advanced prostate cancer-a systematic literature review.

PubMed

Hager, S; Ackermann, C J; Joerger, M; Gillessen, S; Omlin, A

2016-06-01

For men with advanced castration-resistant prostate cancer (CRPC), several treatment options are available, including androgen receptor (AR) pathway inhibitors (abiraterone acetate, enzalutamide), taxanes (docetaxel, cabazitaxel) and the radionuclide (radium-223). However, cross-resistance is a clinically relevant problem. Platinum compounds have been tested in a number of clinical trials in molecularly unselected prostate cancer patients. Advances in CRPC molecular profiling have shown that a significant proportion of patients harbour DNA repair defects, which may serve as predictive markers for sensitivity to platinum agents. To systematically identify and analyse clinical trials that have evaluated platinum agents in advanced prostate cancer patients. PubMed was searched to identify published clinical trials of platinum agents in advanced prostate cancer. The PRIMSA statement was followed for the systematic review process. Identified trials are analysed for study design, statistical plan, assessments of anti-tumour activity and the potential value of predictive biomarkers. A total of 163 references were identified by the literature search and 72 publications that met the selection criteria were included in this review; of these 33 used carboplatin, 27 cisplatin, 6 satraplatin, 4 oxaliplatin and 2 other platinum compounds. Overall, anti-tumour activity varies in the range of 10%-40% for objective response and 20%-70% for PSA decline ≥50%. Response seemed highest for the combinations of carboplatin with taxanes or oxaliplatin with gemcitabine. The interpretation of the clinical data is limited by differences in response criteria used and patient populations studied. Platinum compounds have moderate anti-tumour activity in molecularly unselected patients with advanced prostate cancer. Translational evidence of DNA repair deficiency should be leveraged in future studies to select prostate cancer patients most likely to benefit from platinum-based therapy. © The

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

PubMed Central

Piao, Yun-shang; Wiesenfeld, Paddy; Sprando, Robert; Arnold, Julia T.

2013-01-01

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. PMID:23770322

TGFβ1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

PubMed

Piao, Yun-shang; Wiesenfeld, Paddy; Sprando, Robert; Arnold, Julia T

2013-11-01

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFβ1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFβ1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFβ1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFβ1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3β hydroxysteroid dehydrogenase (HSD), and down-regulation of 17βHSD5, and 17βHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. Published by Elsevier Ltd.

Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer.

PubMed

Kaur, Paranjeet; Khatik, Gopal L

2016-01-01

Prostate cancer (PCa) is a leading cause of death in men worldwide. The main reason for the progression of prostate cancer is identified as over activation of androgen receptor (AR) through androgens. Its development can be diagnosed by monitoring the prostate specific antigen (PSA). Treatment of PCa includes prostatectomy, radiotherapy, and chemotherapy, among them chemotherapy is normally employed in early and advanced prostate cancer. Chemotherapy mainly includes two classes of drugs which are steroidal and non-steroidal antiandrogens. The non-steroidal classes of compounds are preferred over steroidal because they are relatively safe, cost effective and diverse. Non-steroidal drugs are commonly used for the treatment of PCa, however these drugs are associated with serious side effects and acquired resistance. So researchers are working in the direction to develop better analogue which can address the issue related to resistant type of prostate cancer. This review discusses the advancement in the non-steroidal antiandrogens which offers a better potential in the treatment of prostate cancer.

Serum pro-gastrin-releasing peptide (31-98) in benign prostatic hyperplasia and prostatic carcinoma.

PubMed

Nagakawa, Osamu; Furuya, Yuzo; Fujiuchi, Yasuyoshi; Fuse, Hideki

2002-09-01

To clarify whether serum levels of pro-gastrin-releasing peptide (ProGRP) (31-98) could be a useful marker in patients with prostatic carcinoma. GRP is produced and secreted by prostatic neuroendocrine cells. Serum levels of ProGRP(31-98) were measured by enzyme-linked immunosorbent assay in 20 patients with benign prostatic hyperplasia and 107 patients with prostatic carcinoma. The mean serum levels of ProGRP(31-98) in patients with distant metastasis and hormone-resistant prostate cancer were significantly elevated compared with those in patients with organ-confined disease. Significantly elevated levels of ProGRP(31-98) were detected in 9 patients with prostatic carcinoma before any treatment. During hormone-resistant prostate cancer progression, ProGRP(31-98) levels were elevated in 9 patients (23%). Of the 9 patients with Stage D3 and elevated serum ProGRP, 4 had a normal serum prostate-specific antigen level. ProGRP may be a potential tumor marker for prostate cancer. Additional studies in large groups of patients are needed to define the clinical value of ProGRP.

Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models

PubMed Central

Báez-Díaz, Claudia; Sánchez-Margallo, Francisco Miguel

2017-01-01

Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans. PMID:28725598

A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer.

PubMed

Heath, Elisabeth I; Hillman, David W; Vaishampayan, Ulka; Sheng, Shijie; Sarkar, Fazlul; Harper, Felicity; Gaskins, Melvin; Pitot, Henry C; Tan, Winston; Ivy, S Percy; Pili, Roberto; Carducci, Michael A; Erlichman, Charles; Liu, Glenn

2008-12-01

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life. Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%). 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.

Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel

PubMed Central

Harshman, Lauren C.; Chen, Yu-Hui; Liu, Glenn; Carducci, Michael A.; Jarrard, David; Dreicer, Robert; Hahn, Noah; Garcia, Jorge A.; Hussain, Maha; Shevrin, Daniel; Eisenberger, Mario; Kohli, Manish; Plimack, Elizabeth R.; Cooney, Matthew; Vogelzang, Nicholas J.; Picus, Joel; Dipaola, Robert

2018-01-01

Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database (ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/mL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/mL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/mL compared with > 4 ng/mL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/mL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/mL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/mL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood

Characterizing the Hypermutated Subtype of Advanced Prostate Cancer as a Predictive Biomarker for Precision Medicine

DTIC Science & Technology

2017-10-01

goal of this research is to characterize the mechanisms leading to hypermutated prostate cancer and to integrate tumor hypermutation status with... integrate tumor hypermutation status with clinical decision making and therapy to improve the care of men with advanced prostate cancer. Using Next-Gen...preparation of presentations that integrate prostate cancer patient clinical histories with genomic findings 1-36 Yes, see Prostate Precision Tumor

Prostate Cancer Stem-Like Cells | Center for Cancer Research

Cancer.gov

Prostate cancer is the third leading cause of cancer-related death among men, killing an estimated 27,000 men each year in the United States. Men with advanced prostate cancer often become resistant to conventional therapies. Many researchers speculate that the emergence of resistance is due to the presence of cancer stem cells, which are believed to be a small subpopulation of tumor cells that can self-renew and give rise to more differentiated tumor cells. It is thought that these stem cells survive initial therapies (such as chemotherapy and hormone therapy) and then generate new tumor cells that are resistant to these standard treatments. If prostate cancer stem cells could be identified and characterized, it might be possible to design treatments that prevent resistance.

Tissue changes in senescent gerbil prostate after hormone deprivation leads to acquisition of androgen insensitivity

PubMed Central

Campos, Silvana G P; Gonçalves, Bianca F; Scarano, Wellerson R; Corradi, Lara S; Santos, Fernanda C A; Custodio, Ana M G; Vilamaior, Patricia S L; Góes, Rejane M; Taboga, Sebastião R

2010-01-01

The present study examined the response of the prostate epithelium of senescent gerbils submitted to orchiectomy and with or without steroidal blockade. Animals were divided into five groups, all surgically castrated except the control group composed of intact animals. In the experimental groups, doses of flutamide and/or tamoxifen were applied for 1, 3, 7 and 30 days postcastration. The structural methods applied reveal that castration, whether associated or not with anti-steroidal drugs, promoted short- and long-term decrease in wet and relative weights of the prostate. The quantitative decline of epithelial compartment proportion observed at the end of treatment was due to the sum of slight changes in the epithelium and lumen. The apoptotic index had risen significantly at 1 day and declined at 7 days postcastration. Androgen receptor (AR) expression decreased after 3 days of hormonal ablation, coinciding with the highest levels of apoptosis and cell proliferation observed in all treated groups. The majority of cells remained differentiated in all groups due to CK 8/18 expression. Some animals remained with injuries such as carcinomas and adenocarcinomas after hormonal ablation. In the latter a mixture of AR-positive and AR-negative cells was identified. Microinvasive carcinomas found in the group treated for 30 days consisted of PCNA-positive, inflammatory and non-proliferating cells. Low apoptosis incidence and bcl-2 positive cells were observed in these lesions. The treatments promoted a reduction of lesions in older gerbils, but treatment-resistant tumours will improve understanding of the events that lead to hormone resistance. PMID:20353424

Androgenic alopecia may have evolved to protect men from prostate cancer by increasing skin exposure to ultraviolet radiation.

PubMed

Kabai, Peter

2008-01-01

Androgenic alopecia affects populations adapted to colder climate, and individuals at an age and hormonal status susceptible to prostate cancer. Male pattern baldness enhances absorption of UV radiation on the top of the head, an area directly exposed to sunlight during everyday activities. Ultraviolet radiation is reported to reduce the risk of advanced prostate cancer. Here I propose that progression of androgenic alopecia rather than being a risk factor is a finely tuned mechanism evolved to protect against prostate cancer.

Current Standard and Investigational Approaches to the Management of Hormone-Refractory Prostate Cancer

PubMed Central

Mendiratta, Prateek; Armstrong, Andrew J; George, Daniel J

2007-01-01

Prostate cancer is a common cause of death in men and remains incurable in the metastatic setting. In 2004, 2 landmark trials using docetaxel-based chemotherapy, TAX 327 and SWOG 99-16, showed a survival benefit for the first time in metastatic, hormone-refractory prostate cancer. Current research suggests that several distinct mechanisms of androgen-refractory disease may converge in patients with disease progression on androgen deprivation therapy. These findings have identified several potential targets for therapeutic intervention. Current standard and investigational treatment options for this disease are discussed, including chemotherapy and rapidly evolving therapies in phase II/III trials involving antiangiogenic therapies, signal transduction inhibitors, immunomodulatory agents, and nuclear receptor targets. In light of a growing array of treatment options and an increasingly chronic natural history, this review supports a multidisciplinary care approach to these patients, including medical oncologists, urologists, and radiation oncologists, to optimize survival and quality of life. PMID:17387372

Current state of prostate cancer treatment in Jamaica.

PubMed

Morrison, Belinda F; Aiken, William D; Mayhew, Richard

2014-01-01

Prostate cancer is the commonest cancer in Jamaica as well as the leading cause of cancer-related deaths. One report suggested that Jamaica has the highest incidence rate of prostate cancer in the world, with an age-standardised rate of 304/100,000 per year. The Caribbean region is reported to have the highest mortality rate of prostate cancer worldwide. Prostate cancer accounts for a large portion of the clinical practice for health-care practitioners in Jamaica. The Jamaica Urological Society is a professional body comprising 19 urologists in Jamaica who provide most of the care for men with prostate cancer in collaboration with medical oncologists, radiation oncologists, and a palliative care physician. The health-care system is structured in two tiers in Jamaica: public and private. The urologist-to-patient ratio is high, and this limits adequate urological care. Screening for prostate cancer is not a national policy in Jamaica. However, the Jamaica Urological Society and the Jamaica Cancer Society work synergistically to promote screening as well as to provide patient education for prostate cancer. Adequate treatment for localised prostate cancer is available in Jamaica in the forms of active surveillance, nerve-sparing radical retropubic prostatectomy, external beam radiation, and brachytherapy. However, there is a geographic maldistribution of centres that provide prostate cancer treatment, which leads to treatment delays. Also, there is difficulty in affording some treatment options in the private health-care sectors. Androgen deprivation therapy is available for treatment of locally advanced and metastatic prostate cancer and is subsidised through a programme called the National Health Fund. Second-line hormonal agents and chemotherapeutic agents are available but are costly to most of the population. The infrastructure for treatment of prostate cancer in Jamaica is good, but it requires additional technological advances as well as additional specialist

Smooth muscle cell-specific knockout of androgen receptor: a new model for prostatic disease.

PubMed

Welsh, Michelle; Moffat, Lindsey; McNeilly, Alan; Brownstein, David; Saunders, Philippa T K; Sharpe, Richard M; Smith, Lee B

2011-09-01

Androgen-driven stromal-epithelial interactions play a key role in normal prostate development and function as well as in the progression of common prostatic diseases such as benign prostatic hyperplasia and prostate cancer. However, exactly how, and via which cell type, androgens mediate their effects in the adult prostate remains unclear. This study investigated the role for smooth muscle (SM) androgen signaling in normal adult prostate homeostasis and function using mice in which androgen receptor was selectively ablated from prostatic SM cells. In adulthood the knockout (KO) mice displayed a 44% reduction in prostate weight and exhibited histological abnormalities such as hyperplasia, inflammation, fibrosis, and reduced expression of epithelial, SM, and stem cell identify markers (e.g. p63 reduced by 27% and Pten by 31%). These changes emerged beyond puberty and were not explained by changes in serum hormones. Furthermore, in response to exogenous estradiol, adult KO mice displayed an 8.5-fold greater increase in prostate weight than controls and developed urinary retention. KO mice also demonstrated a reduced response to castration compared with controls. Together these results demonstrate that prostate SM cells are vital in mediating androgen-driven stromal-epithelial interactions in adult mouse prostates, determining cell identity and function and limiting hormone-dependent epithelial cell proliferation. This novel mouse model provides new insight into the possible role for SM androgen action in prostate disease.

Development of Personalized Cancer Therapy for Men with Advanced Prostate Cancer

DTIC Science & Technology

2017-10-01

associated with the beta isoform. Based on these studies , we hypothesize that FGFR1 alpha and beta confers different phenotypes to prostate...0.0 calendar Bayer 07/02/2016-12/31/2018 This is an open label study to determine the effect of Alpharadin on the bone marrow microenvironment in...SUPPLEMENTARY NOTES 14. ABSTRACT The purpose of this study is to develop a strategy to identify molecular markers of response of advanced prostate cancer to

Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations.

PubMed

Cook, Michael B; Stanczyk, Frank Z; Wood, Shannon N; Pfeiffer, Ruth M; Hafi, Muhannad; Veneroso, Carmela C; Lynch, Barlow; Falk, Roni T; Zhou, Cindy Ke; Niwa, Shelley; Emanuel, Eric; Gao, Yu-Tang; Hemstreet, George P; Zolfghari, Ladan; Carroll, Peter R; Manyak, Michael J; Sesterhann, Isabell A; Levine, Paul H; Hsing, Ann W

2017-11-01

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r 2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone ( r 2 = 0.10), and then serum estrone and tissue estrone ( r 2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating

[Validation in Spain of the quality of life questionnaire PROSQOLI in patients with advanced prostate cancer].

PubMed

Fernández-Arjona, M; de la Cruz, G; Delgado, J A; Malet, J M; Portillo, J A

2012-01-01

Validation of the PROSQOLI questionnaire adapted to Spanish, pursing an instrument to evaluate, in the common clinical practice, the quality of life in patients with locally advanced or disseminated prostate cancer in our country. A cross-sectional prospective study was designed in 750 patients (150 centers) with disseminated or locally advanced prostate cancer (TNM criterion) who came to the scheduled check-up. Socio-demographic and clinical data of the participants were collected. The subjects filled out the PROSQOLI and EQ-5D questionnaires. The analysis included 561 cases that met the selection criteria. The psychometric characteristics (feasibility, validity and reliability) of the adapted PROSQOLI questionnaire were studied. Mean age was 73.63 (7.59) years. A total of 72.01% of the participants had locally advanced disease. In 28.16%, the primary treatment was radiotherapy, in 12.30% it was prostatectomy. A total of 83.48% received hormone treatment. The mean for each scale of the PROSQOLI questionnaire varied from 68.86 to 74.51. The percentage of no response was less than 3% for each scale. The percentage of subjects with minimum score in any scale was negligible, and the maximum score did not surpass 5%. Mean time to fill out the questionnaire was 109.42 (101.00) seconds. Cronbach's α coefficient was 0.937 and the total item correlation was superior to 0.7 for all the items. Correlations with the EQ-5D questionnaire were moderate. Scores on the questionnaire were associated to all the parameters studied related to the disease. The adapted questionnaire has adequate psychometric properties for its use in research and in the clinical practice. Copyright © 2011 AEU. Published by Elsevier España. All rights reserved.

Sleep Deprivation Alters Rat Ventral Prostate Morphology, Leading to Glandular Atrophy: A Microscopic Study Contrasted with the Hormonal Assays

PubMed Central

Venâncio, Daniel P.; Andersen, Monica L.; Vilamaior, Patricia S. L.; Santos, Fernanda C.; Zager, Adriano; Tufik, Sérgio; Taboga, Sebastião R.; De Mello, Marco T.

2012-01-01

We investigated the effect of 96 h paradoxical sleep deprivation (PSD) and 21-day sleep restriction (SR) on prostate morphology using stereological assays in male rats. After euthanasia, the rat ventral prostate was removed, weighed, and prepared for conventional light microscopy. Microscopic analysis of the prostate reveals that morphology of this gland was altered after 96 h of PSD and 21 days of SR, with the most important alterations occurring in the epithelium and stroma in the course of both procedures compared with the control group. Both 96 h PSD and 21-day SR rats showed lower serum testosterone and higher corticosterone levels than control rats. The significance of our result referring to the sleep deprivation was responsible for deep morphological alterations in ventral prostate tissue, like to castration microscopic modifications. This result is due to the marked alterations in hormonal status caused by PSD and SR. PMID:22927719

NFAT Signaling and the Tumorigenic Microenvironment of the Prostate

DTIC Science & Technology

2016-10-01

Subtask 2: Investigate if NFATc1 promotes the progression of hormone -naïve prostate cancer into castration-resistant prostate cancer 1-18 Drs...combating prostate cancer progression. In order to determine if NFATc1-induced prostate cancer would respond to hormone deprivation therapy, such as...doxycycline (Dox). These tumor cells were then injected to the rear flanks of the nude mice. Recipient mice treated with Dox showed growth of tumor as

Clinical characteristics and prognostic factors of prostate cancer with liver metastases.

PubMed

Wang, HaiTao; Li, BaoGuo; Zhang, PengYu; Yao, YanHong; Chang, JiWu

2014-01-01

Liver metastasis from prostate cancer is uncommon and remains poorly understood. We computer searched the clinical records of all our patients registered into a database to identify patients that presented or developed liver metastases. A total of 27 prostate cancer patients with ultrasound or CT/MR imaging evidence of liver metastases were included in our analysis. The liver metastasis rate from metastatic prostate cancer was 4.29%. Eight (29.63%) patients had previously untreated, hormone-naive prostate cancer (synchronous liver metastases at diagnosis of prostate cancer), whereas 19 (70.37%) patients had already been diagnosed as having hormone-refractory prostate cancer. In the hormone-naive group, the median overall survival after liver metastases diagnosis was 38 months and half of the patients were still alive at the latest follow-up, whereas only 6 months in the hormone-refractory group (p = 0.003). High concentration of serum neuron-specific enolase and previous chemotherapy were associated with a significantly poor overall survival after liver metastases in the hormone-refractory group using Kaplan–Meier curves and logrank tests for univariate analysis.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

PubMed

Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

2017-01-01

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. 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. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

Investigative clinical study on prostate cancer part VI: Follicle-stimulating hormone and the pituitary-testicular-prostate axis at the time of initial diagnosis and subsequent cluster selection of the patient population.

PubMed

Porcaro, Antonio B; Migliorini, Filippo; Petrozziello, Aldo; Sava, Teodoro; Romano, Mario; Caruso, Beatrice; Cocco, Claudio; Ghimenton, Claudio; Zecchinini Antoniolli, Stefano; Lacola, Vincenzo; Rubilotta, Emanuele; Monaco, Carmelo; Comunale, Luigi

2012-01-01

To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13≤FSH/PSA≤0.57), B (0.57prostate cancer and along the pituitary-testis-prostate axis in a patient population FSH significantly correlated to LH, FT and age, and FSH was independently and significantly predicted by both

Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

PubMed

Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

2011-09-15

High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). ©2011 AACR.

Involvement of Novel Multifunction Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis

DTIC Science & Technology

2009-01-01

HPV infection in cervical carcinoma cells . However, this effect is E6 dependent, as p53 could only be degraded by the formation of E6 and E6-AP...and prostate cancer cell proliferation. E6-AP by itself can modulate p53 levels in prostate cancer cells independent of E6. Our data also indicates...p53 levels in prostate glands and prostate cancer cells : E6-AP was initially identified as an E3 ligase which promotes the degradation of p53 during

Detecting prostate cancer and prostatic calcifications using advanced magnetic resonance imaging.

PubMed

Dou, Shewei; Bai, Yan; Shandil, Ankit; Ding, Degang; Shi, Dapeng; Haacke, E Mark; Wang, Meiyun

2017-01-01

Prostate cancer and prostatic calcifications have a high incidence in elderly men. We aimed to investigate the diagnostic capabilities of susceptibility-weighted imaging in detecting prostate cancer and prostatic calcifications. A total number of 156 men, including 34 with prostate cancer and 122 with benign prostate were enrolled in this study. Computed tomography, conventional magnetic resonance imaging, diffusion-weighted imaging, and susceptibility-weighted imaging were performed on all the patients. One hundred and twelve prostatic calcifications were detected in 87 patients. The sensitivities and specificities of the conventional magnetic resonance imaging, apparent diffusion coefficient, and susceptibility-filtered phase images in detecting prostate cancer and prostatic calcifications were calculated. McNemar's Chi-square test was used to compare the differences in sensitivities and specificities between the techniques. The results showed that the sensitivity and specificity of susceptibility-filtered phase images in detecting prostatic cancer were greater than that of conventional magnetic resonance imaging and apparent diffusion coefficient (P < 0.05). In addition, the sensitivity and specificity of susceptibility-filtered phase images in detecting prostatic calcifications were comparable to that of computed tomography and greater than that of conventional magnetic resonance imaging and apparent diffusion coefficient (P < 0.05). Given the high incidence of susceptibility-weighted imaging (SWI) abnormality in prostate cancer, we conclude that susceptibility-weighted imaging is more sensitive and specific than conventional magnetic resonance imaging, diffusion-weighted imaging, and computed tomography in detecting prostate cancer. Furthermore, susceptibility-weighted imaging can identify prostatic calcifications similar to computed tomography, and it is much better than conventional magnetic resonance imaging and diffusion-weighted imaging.

Novel Androgen Deprivation Therapy (ADT) in the Treatment of Advanced Prostate Cancer.

PubMed

Aragon-Ching, Jeanny B; Dahut, William L

2010-07-01

Androgen deprivation therapy has been the mainstay of treatment for advanced and metastatic prostate cancer. The use of novel agents targeting the androgen receptor and its signaling pathways offers a promising approach that is both safe and effective. We describe the rationale behind the use of these compounds in clinical development and the existing challenges as to how best to incorporate these new and emerging therapies in the changing treatment paradigm of metastatic prostate cancer.

A prospective, observational grouped analysis to evaluate the effect of triptorelin on lower urinary tract symptoms in patients with advanced prostate cancer

PubMed Central

Gil, Thierry; Aoun, Fouad; Cabri, Patrick; Maisonobe, Pascal

2015-01-01

Objectives: Few studies have assessed the effect of gonadotropin-releasing hormone (GnRH) agonists, such as triptorelin, on lower urinary tract symptoms (LUTS) in patients with advanced prostate cancer. Therefore, multiple, national observational, noninterventional studies were initiated to assess the effectiveness of triptorelin in reducing moderate or severe LUTS [International Prostate Symptom Score (IPSS) >7] in men with prostate cancer starting triptorelin therapy in clinical practice. Methods: Prospective, noninterventional, multicentre studies of LUTS located in Algeria, Belgium, China, Hungary, Romania and South Korea, in patients who were scheduled to receive triptorelin (3-month extended release or 1-month formulation) in clinical practice. The primary effectiveness endpoint was the proportion of patients with moderate or severe LUTS after 48 weeks as assessed by IPSS. Secondary endpoints included the distribution of IPSS categories, total IPSS and prostate-specific antigen (PSA) levels at baseline, 24 and 48 weeks. Results: In total, 2461 patients were recruited in the studies; 1282 patients had moderate or severe LUTS at baseline (IPSS > 7), received triptorelin and had follow-up IPSS. Mean total IPSS was reduced from 18.2 [95% confidence interval (CI) 17.8–18.5] at baseline to 11.9 (95% CI 11.5–12.3; p < 0.001) and 10.6 (95% CI 10.2–11.0; p < 0.001) at weeks 24 and 48, respectively. Mean PSA levels were reduced from 117.9 ng/ml (95% CI 93.8–141.9) at baseline to 8.5 ng/ml (95% CI 5.2–11.7) and 16.6 ng/ml (95% CI 7.4–25.8) at weeks 24 and 48, respectively. There was a significant correlation between total IPSS change from baseline and PSA change from baseline at weeks 24 and 48 (ρ = 0.3 and 0.2, p < 0.001). Conclusions: The improvement in LUTS in men with locally advanced or metastatic prostate cancer after 24–48 weeks suggests that triptorelin is effective in improving LUTS in this subgroup of patients. PMID:26161142

Detecting prostate cancer and prostatic calcifications using advanced magnetic resonance imaging

PubMed Central

Dou, Shewei; Bai, Yan; Shandil, Ankit; Ding, Degang; Shi, Dapeng; Haacke, E Mark; Wang, Meiyun

2017-01-01

Prostate cancer and prostatic calcifications have a high incidence in elderly men. We aimed to investigate the diagnostic capabilities of susceptibility-weighted imaging in detecting prostate cancer and prostatic calcifications. A total number of 156 men, including 34 with prostate cancer and 122 with benign prostate were enrolled in this study. Computed tomography, conventional magnetic resonance imaging, diffusion-weighted imaging, and susceptibility-weighted imaging were performed on all the patients. One hundred and twelve prostatic calcifications were detected in 87 patients. The sensitivities and specificities of the conventional magnetic resonance imaging, apparent diffusion coefficient, and susceptibility-filtered phase images in detecting prostate cancer and prostatic calcifications were calculated. McNemar's Chi-square test was used to compare the differences in sensitivities and specificities between the techniques. The results showed that the sensitivity and specificity of susceptibility-filtered phase images in detecting prostatic cancer were greater than that of conventional magnetic resonance imaging and apparent diffusion coefficient (P < 0.05). In addition, the sensitivity and specificity of susceptibility-filtered phase images in detecting prostatic calcifications were comparable to that of computed tomography and greater than that of conventional magnetic resonance imaging and apparent diffusion coefficient (P < 0.05). Given the high incidence of susceptibility-weighted imaging (SWI) abnormality in prostate cancer, we conclude that susceptibility-weighted imaging is more sensitive and specific than conventional magnetic resonance imaging, diffusion-weighted imaging, and computed tomography in detecting prostate cancer. Furthermore, susceptibility-weighted imaging can identify prostatic calcifications similar to computed tomography, and it is much better than conventional magnetic resonance imaging and diffusion-weighted imaging. PMID:27004542

A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland

PubMed Central

Pakula, Hubert; Xiang, Dongxi; Li, Zhe

2017-01-01

Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent. PMID:28134791

A Tale of Two Signals: AR and WNT in Development and Tumorigenesis of Prostate and Mammary Gland.

PubMed

Pakula, Hubert; Xiang, Dongxi; Li, Zhe

2017-01-27

Prostate cancer (PCa) is one of the most common cancers and among the leading causes of cancer deaths for men in industrialized countries. It has long been recognized that the prostate is an androgen-dependent organ and PCa is an androgen-dependent disease. Androgen action is mediated by the androgen receptor (AR). Androgen deprivation therapy (ADT) is the standard treatment for metastatic PCa. However, almost all advanced PCa cases progress to castration-resistant prostate cancer (CRPC) after a period of ADT. A variety of mechanisms of progression from androgen-dependent PCa to CRPC under ADT have been postulated, but it remains largely unclear as to when and how castration resistance arises within prostate tumors. In addition, AR signaling may be modulated by extracellular factors among which are the cysteine-rich glycoproteins WNTs. The WNTs are capable of signaling through several pathways, the best-characterized being the canonical WNT/β-catenin/TCF-mediated canonical pathway. Recent studies from sequencing PCa genomes revealed that CRPC cells frequently harbor mutations in major components of the WNT/β-catenin pathway. Moreover, the finding of an interaction between β-catenin and AR suggests a possible mechanism of cross talk between WNT and androgen/AR signaling pathways. In this review, we discuss the current knowledge of both AR and WNT pathways in prostate development and tumorigenesis, and their interaction during development of CRPC. We also review the possible therapeutic application of drugs that target both AR and WNT/β-catenin pathways. Finally, we extend our review of AR and WNT signaling to the mammary gland system and breast cancer. We highlight that the role of AR signaling and its interaction with WNT signaling in these two hormone-related cancer types are highly context-dependent.

EMP combination chemotherapy and low-dose monotherapy in advanced prostate cancer.

PubMed

Kitamura, Tadaichi; Nishimatsu, Hiroaki; Hamamoto, Toshiaki; Tomita, Kyoichi; Takeuchi, Takumi; Ohta, Nobutaka

2002-02-01

Many chemotherapeutic regimens combined with estramustine phosphate (EMP) have been elaborated for the treatment of hormone-refractory prostate cancer over 30 years. However, older EMP-based combination chemotherapies with vinblastine, vinorelbine, doxorubicin or cyclophosphamide showed relatively low PSA response rate (25-58%) accompanied with high toxicities. On the other hand, newly developed EMP-based combination regimens with etoposide, pacitaxel, carboplatin or docetaxel demonstrated promising PSA response rate (43-77%) with moderate to severe toxicity in the rate of thromboembolic event (5-18%) and of neutropenia (9-41%). Treatment-related death was less in the latter combination group (5/615, 0.8%) than that in the former group (3/234, 1.3%). Of note, in the docetaxel combination with EMP, PSA response rate is as high as 77% with high rate (41%) of neutropenia but no treatment-related death was observed. Docetaxel combination with EMP seems to be the best regimen, though not completely justified by randomized trials, to be selected in the modern era, which will be followed by paclitaxel, carboplatin and EMP combination with PSA response rate of 71%. In addition, an interim report in 83 patients was presented. They were not consecutively enrolled but were treated on low-dose EMP monotherapy for previously untreated advanced prostate cancer in Department of Urology of Tokyo University and our 21 affiliated hospitals. Overall PSA response rate was as high as 93.4% out of 76 assessable patients. However, overall toxicity rate was abnormally high (39.5%) with drug discontinuation rate of 32.1%. The reason of low drug compliance may be attributed to gastrointestinal symptoms. To overcome the low drug compliance, appropriate patients for EMP administration should be selected by using gene analysis on the basis of sophisticated tailor-made medicine.

Profiles of dyadic adjustment for advanced prostate cancer to inform couple-based intervention.

PubMed

Elliott, Kate-Ellen J; Scott, Jennifer L; Monsour, Michael; Nuwayhid, Fadi

2015-01-01

The purpose of the study is to describe from a relational perspective, partners' psychological adjustment, coping and support needs for advanced prostate cancer. A mixed methods design was adopted, employing triangulation of qualitative and quantitative data, to produce dyadic profiles of adjustment for six couples recruited from the urology clinics of local hospitals in Tasmania, Australia. Dyads completed a video-taped communication task, semi-structured interview and standardised self-report questionnaires. Themes identified were associated with the dyadic challenges of the disease experience (e.g. relationship intimacy, disease progression and carer burden). Couples with poor psychological adjustment profiles had both clinical and global locus of distress, treatment side-effects, carer burden and poor general health. Resilient couples demonstrated relationship closeness and adaptive cognitive and behavioural coping strategies. The themes informed the adaption of an effective program for couples coping with women's cancers (CanCOPE, to create a program for couples facing advanced prostate cancer (ProCOPE-Adv). Mixed method results inform the development of psychological therapy components for couples coping with advanced prostate cancer. The concomitance of co-morbid health problems may have implications for access and engagement for older adult populations in face-to-face intervention.

Protopine, a novel microtubule-stabilizing agent, causes mitotic arrest and apoptotic cell death in human hormone-refractory prostate cancer cell lines.

PubMed

Chen, Chun-Han; Liao, Cho-Hwa; Chang, Ya-Ling; Guh, Jih-Hwa; Pan, Shiow-Lin; Teng, Che-Ming

2012-02-01

In this study, we investigated the anticancer effect of protopine on human hormone-refractory prostate cancer (HRPC) cells. Protopine exhibited an anti-proliferative effect by induction of tubulin polymerization and mitotic arrest, which ultimately led to apoptotic cell death. The data suggest that protopine increased the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex and that contributed to cell apoptosis by modulating mitochondria-mediated signaling pathways, such as Bcl-2 phosphorylation and Mcl-1 down-regulation. In conclusion, the data suggest that protopine is a novel microtubule stabilizer with anticancer activity in HRPC cells through apoptotic pathway by modulating Cdk1 activity and Bcl-2 family of proteins. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers

PubMed Central

Abderrahman, Balkees; Curpan, Ramona F; Hawsawi, Yousef M; Fan, Ping; Jordan, V Craig

2018-01-01

Prostate and breast cancer are the two cancers with the highest incidence in men and women, respectively. Here, we focus on the known biology of acquired resistance to antihormone therapy of prostate and breast cancer and compare laboratory and clinical similarities in the evolution of the disease. Laboratory studies and clinical observations in prostate and breast cancer demonstrate that cell selection pathways occur during acquired resistance to antihormonal therapy. Following sex steroid deprivation, both prostate and breast cancer models show an initial increased acquired sensitivity to the growth potential of sex steroids. Subsequently, prostate and breast cancer cells either become dependent upon the antihormone treatment or grow spontaneously in the absence of hormones. Paradoxically, the physiologic sex steroids now kill a proportion of selected, but vulnerable, resistant tumor cells. The sex steroid receptor complex triggers apoptosis. We draw parallels between acquired resistance in prostate and breast cancer to sex steroid deprivation. Clinical observations and patient trials confirm the veracity of the laboratory studies. We consider therapeutic strategies to increase response rates in clinical trials of metastatic disease that can subsequently be applied as a preemptive salvage adjuvant therapy. The goal of future advances is to enhance response rates and deploy a safe strategy earlier in the treatment plan to save lives. The introduction of a simple evidence-based enhanced adjuvant therapy as a global healthcare strategy has the potential to control recurrence, reduce hospitalization, reduce healthcare costs and maintain a healthier population that contributes to society. PMID:29162647

The prospect of gene therapy for prostate cancer: update on theory and status.

PubMed

Koeneman, K S; Hsieh, J T

2001-09-01

Molecularly based novel therapeutic agents are needed to address the problem of locally recurrent, or metastatic, advanced hormone-refractory prostate cancer. Recent basic science advances in mechanisms of gene expression, vector delivery, and targeting have rendered clinically relevant gene therapy to the prostatic fossa and distant sites feasible in the near future. Current research and clinical investigative efforts involving methods for more effective vector delivery and targeting, with enhanced gene expression to selected (specific) sites, are reviewed. These areas of research involve tissue-specific promoters, transgene exploration, vector design and delivery, and selective vector targeting. The 'vectorology' involved mainly addresses selective tissue homing with ligands, mechanisms of innate immune system evasion for durable transgene expression, and the possibility of repeat administration.

Novel Androgen Deprivation Therapy (ADT) in the Treatment of Advanced Prostate Cancer

PubMed Central

Aragon-Ching, Jeanny B.; Dahut, William L.

2011-01-01

Androgen deprivation therapy has been the mainstay of treatment for advanced and metastatic prostate cancer. The use of novel agents targeting the androgen receptor and its signaling pathways offers a promising approach that is both safe and effective. We describe the rationale behind the use of these compounds in clinical development and the existing challenges as to how best to incorporate these new and emerging therapies in the changing treatment paradigm of metastatic prostate cancer. PMID:21922023

Inhibitory Ah Receptor-Androgen Receptor Crosstalk in Prostate Cancer

DTIC Science & Technology

2006-02-01

Development of a hammerhead ribozyme against bcl-2. I. Preliminary evaluation of a potential gene therapeutic agent for hormone-refractory human prostate...therapeutic implications, N. Engl. J. Med. 285 (1971) 1182–1186. [14] T. Dorai, C.A. Olsson, A.E. Katz, R. Buttyan, Development of a hammerhead ... ribozyme against bcl-2. I. Preliminary evaluation of a potential gene therapeutic agent for hormone-refractory human prostate cancer, Prostate 32 (1997) 246

[Advanced Prostate Cancer Consensus Conference 2017 : Discussion of the recommendations for diagnosis and treatment of metastatic prostate cancer by a German panel of experts].

PubMed

Schostak, M; König, F; Bögemann, M; Goebell, P; Hammerer, P; Machtens, S; Schwentner, C; Thomas, C; von Amsberg, G; von Rundstedt, F-C; Heidenreich, A

2018-05-28

In March 2017 the 'Advanced Prostate Cancer Consensus Conference' (APCCC) took place in St. Gallen (Switzerland). The APCCC-panelists are internationally well known experts. With the actual data in mind they discussed treatment options for patients with advanced prostate cancer in order to update the international APCCC-recommendations from the previous meeting in 2015. Recently these consensus recommendations have been published in "European Urology".A group of German experts discussed this year APCCC-votes during the meeting and the recommendations that were concluded from the votes from the German perspective. Reasons for an additional German discussion are country-specific variations that may have influenced the APCCC-votes und recommendations. Due to the concept of the APCCC-meeting the wording of the questions could not always be as necessary.One focus of this year consensus discussion was the treatment of metastatic castration-naive prostate cancer (mCNPC). There are new data which may also influence the therapeutic situation of patients with metastatic castration-resistant prostate cancer (mCRPC). Further points of discussion were the impact of new imaging procedures in the clinical setting as well as the treatment of oligometastatic prostate cancer.

[Molecular biology of castration-resistant prostate cancer].

PubMed

Doucet, Ludovic; Terrisse, Safae; Gauthier, Hélène; Pouessel, Damien; Le Maignan, Christine; Teixeira, Luis; Culine, Stéphane

2015-06-01

Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade. Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

PubMed

Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Studying circulating prostate cancer cells by in-vivo flow cytometer

NASA Astrophysics Data System (ADS)

Guo, Jin; Gu, Zhengqin; Chen, Tong; Wang, Cheng; Wei, Xunbin

2012-03-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. We have measured the depletion kinetics of cancer cells with different metastatic potential. Interestingly, more invasive PC-3 prostate cancer cells are depleted faster from the circulation than LNCaP cells.

Age-dependent associations between androgenetic alopecia and prostate cancer risk.

PubMed

Muller, David C; Giles, Graham G; Sinclair, Rod; Hopper, John L; English, Dallas R; Severi, Gianluca

2013-02-01

Both prostate cancer and androgenetic alopecia are strongly age-related conditions that are considered to be androgen dependent, but studies of the relationship between them have yielded inconsistent results. We aimed to assess whether androgenetic alopecia at ages 20 and 40 years are associated with risk of prostate cancer. At a follow-up of the Melbourne Collaborative Cohort Study, men were asked to assess their hair pattern at ages 20 and 40 years relative to eight categories in showcards. Cases were men notified to the Victorian Cancer Registry with prostate cancer diagnosed between cohort enrollment (1990-1994) and follow-up attendance (2003-2009). Flexible parametric survival models were used to estimate age-varying HRs and predicted cumulative probabilities of prostate cancer by androgenetic alopecia categories. Of 9,448 men that attended follow-up and provided data on androgenetic alopecia, we identified 476 prostate cancer cases during a median follow-up of 11 years four months. Cumulative probability of prostate cancer was greater at all ages up to 76 years, for men with vertex versus no androgenetic alopecia at age of 40 years. At age of 76 years, the estimated probabilities converged to 0.15. Vertex androgenetic alopecia at 40 years was also associated with younger age of diagnosis for prostate cancer cases. Vertex androgenetic alopecia at age of 40 years might be a marker of increased risk of early-onset prostate cancer. If confirmed, these results suggest that the apparently conflicting findings of previous studies might be explained by failure to adequately model the age-varying nature of the association between androgenetic alopecia and prostate cancer.

Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer

PubMed Central

Liao, Zhiyong; Lutz, Jacqueline; Nevalainen, Marja T.

2009-01-01

Prostate cancer is the most common non-cutaneous cancer in Western males. The majority of prostate cancer fatalities are caused by development of castration-resistant growth and metastatic spread of the primary tumor. The average duration of the response of primary prostate cancer to hormonal ablation is less than 3 years, and 75% of prostate cancers in the United States progress to hormone-refractory disease. The existing pharmacological therapies for metastatic and/or hormone-refractory prostate cancer do not provide significant survival benefit. This review summarizes the importance of transcription factor Stat5 signaling in the pathogenesis of prostate cancer and discusses the molecular basis why inhibition of Stat5a/b could be used as a therapeutic strategy for prostate cancer. PMID:19914392

Rationale for Modernising Imaging in Advanced Prostate Cancer.

PubMed

Padhani, Anwar R; Lecouvet, Frederic E; Tunariu, Nina; Koh, Dow-Mu; De Keyzer, Frederik; Collins, David J; Sala, Evis; Fanti, Stefano; Vargas, H Alberto; Petralia, Giuseppe; Schlemmer, Heinz Peter; Tombal, Bertrand; de Bono, Johann

2017-04-01

To effectively manage patients with advanced prostate cancer (APC), it is essential to have accurate, reproducible, and validated methods for detecting and quantifying the burden of bone and soft tissue metastases and for assessing their response to therapy. Current standard of care imaging with bone and computed tomography (CT) scans have significant limitations for the assessment of bone metastases in particular. We aimed to undertake a critical comparative review of imaging methods used for diagnosis and disease monitoring of metastatic APC from the perspective of their availability and ability to assess disease presence, extent, and response of bone and soft tissue disease. An expert panel of radiologists, nuclear medicine physicians, and medical physicists with the greatest experience of imaging in advanced prostate cancer prepared a review of the practicalities, performance, merits, and limitations of currently available imaging methods. Meta-analyses showed that positron emission tomography (PET)/CT with different radiotracers and whole-body magnetic resonance imaging (WB-MRI) are more accurate for bone lesion detection than CT and bone scans (BSs). At a patient level, the pooled sensitivities for bone disease by using choline (CH)-PET/CT, WB-MRI, and BS were 91% (95% confidence interval [CI], 83-96%), 97% (95% CI, 91-99%), and 79% (95% CI, 73-83%), respectively. The pooled specificities for bone metastases detection using CH-PET/CT, WB-MRI, and BS were 99% (95% CI, 93-100%), 95% (95% CI, 90-97%), and 82% (95% CI, 78-85%), respectively. The ability of PET/CT and WB-MRI to assess therapeutic benefits is promising but has not been comprehensively evaluated. There is variability in the cost, availability, and quality of PET/CT and WB-MRI. Standardisation of acquisition, interpretation, and reporting of WB-MRI and PET/CT scans is required to assess the performance of these techniques in clinical trials of treatment approaches in APC. PET/CT and whole-body MRI

Hormone therapy for prostate cancer

MedlinePlus

... be used: Before radiation or surgery to help shrink tumors Along with radiation therapy for cancer that ... of most androgens in the body. This also shrinks or stops prostate cancer from growing. While effective, ...

Vinclozolin Exposure in Utero Induces Postpubertal Prostatitis and Reduces Sperm Production via a Reversible Hormone-Regulated Mechanism

PubMed Central

Cowin, Prue A.; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K.; Foster, Paul M. D.; Scott, Hamish S.; Risbridger, Gail P.

2010-01-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-κB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, −3A, −3B, and −3L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-κB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression. PMID:20056826

Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism.

PubMed

Cowin, Prue A; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K; Foster, Paul M D; Scott, Hamish S; Risbridger, Gail P

2010-02-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-kappaB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, -3A, -3B, and -3L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-kappaB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression.

Management of advanced prostate cancer in senior adults: the new landscape.

PubMed

Aapro, Matti S

2012-01-01

The landscape of treatment for advanced prostate cancer is continually evolving as new therapies are developed and guidelines are constantly updated. However, the management of older men with advanced disease is not optimal. Many men are denied chemotherapy based on their chronological age, not their health status. Androgen-deprivation therapy (ADT) remains the mainstay of first-line treatment of advanced disease. Once the disease becomes resistant to castration, docetaxel-based chemotherapy is the regulatory-approved standard of care, irrespective of age. The place of weekly docetaxel in patients with poor performance status and signs of frailty has to be further evaluated in clinical studies. New treatments are now available, or on the horizon, for disease that progresses during or after docetaxel therapy. Cabazitaxel and abiraterone have been shown to prolong survival, irrespective of age, and are already in clinical use having received regulatory approval. The optimal sequence for these two agents is still unknown, although there is some indication that in patients predicted to be poor responders to abiraterone (high Gleason score, progression during docetaxel therapy, rapid progression to castrate-resistant prostate cancer with ADT) cabazitaxel should be the preferred choice. Further advances are being investigated, with promising data reported from phase III trials.

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

PubMed Central

Bitting, Rhonda L.; Schaeffer, Daneen; Somarelli, Jason A.; Garcia-Blanco, Mariano A.

2014-01-01

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches. PMID:24414193

Pretreatment tables predicting pathologic stage of locally advanced prostate cancer.

PubMed

Joniau, Steven; Spahn, Martin; Briganti, Alberto; Gandaglia, Giorgio; Tombal, Bertrand; Tosco, Lorenzo; Marchioro, Giansilvio; Hsu, Chao-Yu; Walz, Jochen; Kneitz, Burkhard; Bader, Pia; Frohneberg, Detlef; Tizzani, Alessandro; Graefen, Markus; van Cangh, Paul; Karnes, R Jeffrey; Montorsi, Francesco; van Poppel, Hein; Gontero, Paolo

2015-02-01

Pretreatment tables for the prediction of pathologic stage have been published and validated for localized prostate cancer (PCa). No such tables are available for locally advanced (cT3a) PCa. To construct tables predicting pathologic outcome after radical prostatectomy (RP) for patients with cT3a PCa with the aim to help guide treatment decisions in clinical practice. This was a multicenter retrospective cohort study including 759 consecutive patients with cT3a PCa treated with RP between 1987 and 2010. Retropubic RP and pelvic lymphadenectomy. Patients were divided into pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (GS) subgroups. These parameters were used to construct tables predicting pathologic outcome and the presence of positive lymph nodes (LNs) after RP for cT3a PCa using ordinal logistic regression. In the model predicting pathologic outcome, the main effects of biopsy GS and pretreatment PSA were significant. A higher GS and/or higher PSA level was associated with a more unfavorable pathologic outcome. The validation procedure, using a repeated split-sample method, showed good predictive ability. Regression analysis also showed an increasing probability of positive LNs with increasing PSA levels and/or higher GS. Limitations of the study are the retrospective design and the long study period. These novel tables predict pathologic stage after RP for patients with cT3a PCa based on pretreatment PSA level and biopsy GS. They can be used to guide decision making in men with locally advanced PCa. Our study might provide physicians with a useful tool to predict pathologic stage in locally advanced prostate cancer that might help select patients who may need multimodal treatment. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Leuprorelin, triptorelin: new indications. Locally advanced prostate cancer: minimally assessed me-toos.

PubMed

2007-12-01

Unlike goserelin, leuprorelin and triptorelin have not been assessed for their impact on survival in patients with locally advanced prostate cancer. The main adverse effects of these two drugs are similar, but convenience of use differs.

Mortality Among Men with Advanced Prostate Cancer Excluded from the ProtecT Trial.

PubMed

Johnston, Thomas J; Shaw, Greg L; Lamb, Alastair D; Parashar, Deepak; Greenberg, David; Xiong, Tengbin; Edwards, Alison L; Gnanapragasam, Vincent; Holding, Peter; Herbert, Phillipa; Davis, Michael; Mizielinsk, Elizabeth; Lane, J Athene; Oxley, Jon; Robinson, Mary; Mason, Malcolm; Staffurth, John; Bollina, Prasad; Catto, James; Doble, Andrew; Doherty, Alan; Gillatt, David; Kockelbergh, Roger; Kynaston, Howard; Prescott, Steve; Paul, Alan; Powell, Philip; Rosario, Derek; Rowe, Edward; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E

2017-03-01

Early detection and treatment of asymptomatic men with advanced and high-risk prostate cancer (PCa) may improve survival rates. To determine outcomes for men diagnosed with advanced PCa following prostate-specific antigen (PSA) testing who were excluded from the ProtecT randomised trial. Mortality was compared for 492 men followed up for a median of 7.4 yr to a contemporaneous cohort of men from the UK Anglia Cancer Network (ACN) and with a matched subset from the ACN. PCa-specific and all-cause mortality were compared using Kaplan-Meier analysis and Cox's proportional hazards regression. Of the 492 men excluded from the ProtecT cohort, 37 (8%) had metastases (N1, M0=5, M1=32) and 305 had locally advanced disease (62%). The median PSA was 17μg/l. Treatments included radical prostatectomy (RP; n=54; 11%), radiotherapy (RT; n=245; 50%), androgen deprivation therapy (ADT; n=122; 25%), other treatments (n=11; 2%), and unknown (n=60; 12%). There were 49 PCa-specific deaths (10%), of whom 14 men had received radical treatment (5%); and 129 all-cause deaths (26%). In matched ProtecT and ACN cohorts, 37 (9%) and 64 (16%), respectively, died of PCa, while 89 (22%) and 103 (26%) died of all causes. ProtecT men had a 45% lower risk of death from PCa compared to matched cases (hazard ratio 0.55, 95% confidence interval 0.38-0.83; p=0.0037), but mortality was similar in those treated radically. The nonrandomised design is a limitation. Men with PSA-detected advanced PCa excluded from ProtecT and treated radically had low rates of PCa death at 7.4-yr follow-up. Among men who underwent nonradical treatment, the ProtecT group had a lower rate of PCa death. Early detection through PSA testing, leadtime bias, and group heterogeneity are possible factors in this finding. Prostate cancer that has spread outside the prostate gland without causing symptoms can be detected via prostate-specific antigen testing and treated, leading to low rates of death from this disease. Copyright �

Estrogen action and prostate cancer

PubMed Central

Nelles, Jason L; Hu, Wen-Yang; Prins, Gail S

2011-01-01

Early work on the hormonal basis of prostate cancer focused on the role of androgens, but more recently estrogens have been implicated as potential agents in the development and progression of prostate cancer. In this article, we review the epidemiological, laboratory and clinical evidence that estrogen may play a causative role in human prostate cancer, as well as rodent and grafted in vivo models. We then review recent literature highlighting potential mechanisms by which estrogen may contribute to prostate cancer, including estrogenic imprinting and epigenetic modifications, direct genotoxicity, hyperprolactinemia, inflammation and immunologic changes, and receptor-mediated actions. We discuss the work performed so far separating the actions of the different known estrogen receptors (ERs), ERα and ERβ, as well as G-protein-coupled receptor 30 and their specific roles in prostate disease. Finally, we predict that future work in this field will involve more investigations into epigenetic changes, experiments using new models of hormonal dysregulation in developing human prostate tissue, and continued delineation of the roles of the different ER subtypes, as well as their downstream signaling pathways that may serve as therapeutic targets. PMID:21765856

Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells

DTIC Science & Technology

2005-03-01

Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Dr. Dean Tang...SUBTITLE 5a. CONTRACT NUMBER Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells 5b. GRANT NUMBER DAMD17-03-1...Unlimited 13. SUPPLEMENTARY NOTES Original contains colored plates: ALL DTIC reproductions will be in black and white. 14. ABSTRACT

Involvement of Novel Multifunction Steroid Hormone Receptor Coactivator, E6-Associated Protein, in Prostate Gland Tumorigenesis

DTIC Science & Technology

2010-01-01

identified as an E3 ligase which promotes the degradation of p53 during HPV infection in cervical carcinoma cells . However, this effect is E6 dependent, as...LNCaP cells . In this report I have provided evidence that E6-AP plays a vital role in the prostate gland growth and prostate cancer cell proliferation...E6-AP by itself can modulate p53 levels in prostate cancer cells independent of E6. Our data also indicates that over expression of E6-AP could

Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia.

PubMed

Nejishima, Hiroaki; Yamamoto, Noriko; Suzuki, Mika; Furuya, Kazuyuki; Nagata, Naoya; Yamada, Shizuo

2012-10-01

Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. Copyright © 2012 Wiley Periodicals, Inc.

Serum Testosterone Levels in Prostate Cancer Patients Undergoing Luteinizing Hormone-Releasing Hormone Agonist Therapy.

PubMed

Morote, Juan; Comas, Inma; Planas, Jacques; Maldonado, Xavier; Celma, Ana; Placer, José; Ferrer, Roser; Carles, Joan; Regis, Lucas

2018-04-01

Serum testosterone measurement is recommended to assess the efficacy of androgen deprivation therapy (ADT) and to diagnose castration resistance in patients with prostate cancer (PCa). Currently, the accepted castrate level of serum testosterone is 50 ng/dL. Liquid chromatography and tandem mass spectrometry (LC MSMS) is the appropriate method to measure testosterone, especially at low levels. However, worldwide, chemiluminescent assays (CLIAs) are used in clinical laboratories, despite their lack of accuracy and reproducibility, because they are automatable, fast, sensitive, and inexpensive. We compared serum testosterone levels measured using LC MSMS and CLIAs in 126 patients with PCa undergoing luteinizing hormone-releasing hormone (LHRH) agonist therapy. The median serum testosterone level was 14.0 ng/dL (range, 2.0-67.0 ng/dL) with LC MSMS and 31.9 ng/dL (range, 10.0-91.6 ng/dL) with CLIA (P < .001). The serum testosterone levels, measured using LC MSMS, were < 20 ng/dL in 83 patients (65.9%), 20 to 50 ng/dL in 40 (31.7%), and > 50 ng/dL in 3 patients (2.4%). These ranges were found in 34 (27%), 72 (57.1%), and 20 (15.9%) patients when testosterone was measured using CLIA (P < .001). The castrate level of serum testosterone using LC MSMS and CLIA was 39.8 ng/dL (95% confidence interval [CI], 37.1-43.4 ng/dL) and 66.5 ng/dL (95% CI, 62.3-71.2 ng/dL), respectively. We found that CLIA overestimated the testosterone levels in PCa patients undergoing LHRH agonist therapy. Thus, the castration level was incorrectly considered inadequate with CLIA in almost 15% of patients. The true castration level of serum testosterone using an appropriate method is < 50 ng/dL. Copyright © 2017 Elsevier Inc. All rights reserved.

Recent advances in treatment for Benign Prostatic Hyperplasia.

PubMed

van Rij, Simon; Gilling, Peter

2015-01-01

Clinical benign prostatic hyperplasia (BPH), often identified as a worsening ability of a male to pass urine, is a significant problem for men in our society. In 2015, the use of personalised medicine is tailoring treatment to individual patient needs and to genetic characteristics. Technological advances in surgical treatment are changing the way BPH is treated and are resulting in less morbidity. The future of BPH treatments is exciting, and a number of novel techniques are currently under clinical trial.

Abiraterone acetate/androgen deprivation therapy combination versus docetaxel/androgen deprivation therapy combination in advanced hormone-sensitive prostate cancer: a network meta-analysis on safety and efficacy.

PubMed

Kassem, Loay; Shohdy, Kyrillus S; Abdel-Rahman, Omar

2018-05-01

A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations. PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed. Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545-0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98-1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075). Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between

Cabazitaxel Plus Prednisone With Octreotide For Castration-Resistant Prostate Cancer (CRPC) Previously Treated With Docetaxel

ClinicalTrials.gov

2014-11-21

Diarrhea; Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer; Stage III Prostate Cancer; Stage IV Prostate Cancer

Behavioral stress accelerates prostate cancer development in mice

PubMed Central

Hassan, Sazzad; Karpova, Yelena; Baiz, Daniele; Yancey, Dana; Pullikuth, Ashok; Flores, Anabel; Register, Thomas; Cline, J. Mark; D’Agostino, Ralph; Danial, Nika; Datta, Sandeep Robert; Kulik, George

2013-01-01

Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress–prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog–deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling. PMID:23348742

Targeted BikDD expression kills androgen-dependent and castration-resistant prostate cancer cells

PubMed Central

Xie, Xiaoming; Kong, Yanan; Tang, Hailin; Yang, Lu; Hsu, Jennifer L; Hung, Mien-Chie

2014-01-01

Targeted gene therapy is a promising approach for treating prostate cancer after the discovery of prostate cancer-specific promoters such as prostate-specific antigen, rat probasin, and human glandular kallikrein. However, these promoters are androgen-dependent, and after castration or androgen ablation therapy, they become much less active or sometimes inactive. Importantly, the disease will inevitably progress from androgen-dependent (ADPC) to castration-resistant prostate cancer (CRPC) at which treatments fail and high mortality ensues. Therefore, it is critical to develop a targeted gene therapy strategy that is effective in both ADPC and CRPC to eradicate recurrent prostate tumors. The human telomerase reverse transcriptase-VP16-Gal4-WPRE integrated systemic amplifier composite (T-VISA) vector we previously developed which targets transgene expression in ovarian and breast cancer is also active in prostate cancer. To further improve its effectiveness based on androgen response in ADPC progression, the ARR2 element (two copies of androgen response region from rat probasin promoter) was incorporated into T-VISA to produce AT-VISA. Under androgen analog (R1881) stimulation, the activity of AT-VISA was increased to a level greater than or comparable to the cytomegalovirus (CMV) promoter in ADPC and CRPC cells, respectively. Importantly, AT-VISA demonstrated little or no expression in normal cells. Systemic administration of AT-VISA-BikDD encapsulated in liposomes repressed prostate tumor growth and prolonged mouse survival in orthotopic animal models as well as in the transgenic adenocarcinoma mouse prostate model, indicating that AT-VISA-BikDD has therapeutic potential to treat ADPC and CRPC safely and effectively in preclinical setting. PMID:24785255

LHRH Agonists for the Treatment of Prostate Cancer: 2012

PubMed Central

Lepor, Herbert; Shore, Neal D

2012-01-01

The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge (“clinical flare”) and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT. PMID:23172994

Physical Activity, Sedentary Behavior and Health Related Quality of Life in Prostate Cancer Survivors in the Health Professionals Follow-up Study

PubMed Central

Phillips, Siobhan M.; Stampfer, Meir J.; Chan, June M.; Giovannucci, Edward L.; Kenfield, Stacey A.

2015-01-01

Purpose Many prostate cancer survivors experience compromised health-related quality of life (HRQOL) as a result of prostate cancer. We examined relationships between types and intensities of activity and sedentary behavior and prostate cancer-related HRQOL, overall, and by demographic, disease, and treatment characteristics. Methods Associations between post-diagnosis activity and sedentary behavior and HRQOL domains (urinary incontinence, urinary irritation/obstruction, bowel, sexual and vitality/hormonal) were prospectively examined in men diagnosed with non-metastatic prostate cancer in the Health Professionals Follow-up Study (n=1917) using generalized linear models. Results After adjusting for potential confounders, higher duration of total, non-vigorous, and walking activity was associated with higher vitality/hormonal functioning scores (p-trends,< 0.0001). Effects were small (d= 0.16–0.20), but approached clinical significance for men in the highest versus lowest activity categories. Survivors who walked ≥90 minutes/week at a normal pace, or faster, reported higher hormone/vitality scores (p=0.001) than men walking <90 minutes at an easy pace. Weight lifting was associated with increased urinary incontinence (p-trend,0.02). Total activity was associated with higher hormone/vitality functioning in men who were ≥5 years post-treatment, had more advanced disease (Gleason score ≥7), and had ≥1 comorbid condition. No relationships were observed between vigorous activity or sedentary behavior and HRQOL. Conclusions Increased duration of non-vigorous activity and walking post-diagnosis was positively associated with better hormone/vitality functioning. Specifically, engaging in ≥5 hours of non-vigorous activity or ≥3 hours of walking per week may be beneficial. Implications for Cancer Survivors Encouraging men to engage in non-vigorous activity and walking may be helpful for managing prostate cancer-related HRQOL. PMID:25876555

Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells12

PubMed Central

Wittig-Blaich, Stephanie M; Kacprzyk, Lukasz A; Eismann, Thorsten; Bewerunge-Hudler, Melanie; Kruse, Petra; Winkler, Eva; Strauss, Wolfgang S L; Hibst, Raimund; Steiner, Rudolf; Schrader, Mark; Mertens, Daniel; Sültmann, Holger; Wittig, Rainer

2011-01-01

The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases. PMID:21750652

Associations of serum sex steroid hormones and 5α-androstane-3α,17β-diol glucuronide concentrations with prostate cancer risk among men treated with finasteride

PubMed Central

Kristal, Alan R.; Till, Cathee; Tangen, Catherine M.; Goodman, Phyllis J.; Neuhouser, Marian L.; Stanczyk, Frank Z.; Chu, Lisa W.; Patel, Sherfaraz K.; Thompson, Ian; Reichardt, Juergen K.; Hoque, Ashraful; Platz, Elizabeth A.; Figg, William D.; Van Bokhoven, Adrie; Lippman, Scott M.; Hsing, Ann W

2012-01-01

BACKGROUND Finasteride, an inhibitor of 5 α-reductase (Type II), lowers intraprostatic dihydrotestosterone (DHT), which is reflected in serum as reduced 5α-androstane-3α,17β-diol glucuronide (3α-dG). It also modestly increases serum testosterone (T), estrone (E1) and estradiol (E2). In this altered hormonal milieu, it is unknown whether serum concentrations of these hormones are associated with prostate cancer risk. METHODS In this nested case-control study of men in the finasteride arm of the Prostate Cancer Prevention Trial, sex steroid hormones and sex hormone binding globulin (SHBG) were measured at baseline and approximately 3-years post-treatment in 553 prostate cancer cases and 694 controls. RESULTS Median post-treatment changes in concentrations of 3α-dG, T, E1, and E2 were −73.8%, +10.1%, +11.2%, and +7.5% (all p<0.001), respectively. Neither the pre- nor post-treatment concentrations of 3α-dG, nor its change, were associated with risk. Pre-treatment, high concentrations of E1 and low concentrations of T were associated with increased cancer risk (Odds Ratio[95% CI] quartile 4 vs 1: 1.38[0.99–1.93] ptrend=0.03; 0.64 [0.43–0.93] ptrend=0.07, respectively). Post-treatment, high concentrations of both E1 and E2 and were associated with increased cancer risk (OR[95% CI] quartile 4 vs 1: 1.54[1.09–2.17] ptrend=0.03; 1.49[1.07–2.07] ptrend=0.02, respectively). CONCLUSIONS Among finasteride-treated men, concentrations of 3α-dG were not associated with total or Gleason grades 2–6, 7–10 or 8–10 cancer. High serum estrogens may increase cancer risk when intraprostatic DHT is pharmacologically lowered. IMPACT Low post-treatment serum estrogens may identify men more likely to benefit from use of finasteride to prevent prostate cancer. PMID:22879203

The microbiome in prostate inflammation and prostate cancer.

PubMed

Porter, Corey M; Shrestha, Eva; Peiffer, Lauren B; Sfanos, Karen S

2018-05-23

The human microbiome may influence prostate cancer initiation and/or progression through both direct and indirect interactions. To date, the majority of studies have focused on direct interactions including the influence of prostate infections on prostate cancer risk and, more recently, on the composition of the urinary microbiome in relation to prostate cancer. Less well understood are indirect interactions of the microbiome with prostate cancer, such as the influence of the gastrointestinal or oral microbiota on pro- or anti-carcinogenic xenobiotic metabolism, and treatment response. We review the literature to date on direct and indirect interactions of the microbiome with prostate inflammation and prostate cancer. Emerging studies indicate that the microbiome can influence prostate inflammation in relation to benign prostate conditions such as prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia, as well as in prostate cancer. We provide evidence that the human microbiome present at multiple anatomic sites (urinary tract, gastrointestinal tract, oral cavity, etc.) may play an important role in prostate health and disease. In health, the microbiome encourages homeostasis and helps educate the immune system. In dysbiosis, a systemic inflammatory state may be induced, predisposing remote anatomical sites to disease, including cancer. The microbiome's ability to affect systemic hormone levels may also be important, particularly in a disease such as prostate cancer that is dually affected by estrogen and androgen levels. Due to the complexity of the potential interconnectedness between prostate cancer and the microbiome, it is vital to further explore and understand the relationships that are involved.

Prostate organogenesis: tissue induction, hormonal regulation and cell type specification

PubMed Central

Toivanen, Roxanne

2017-01-01

Prostate organogenesis is a complex process that is primarily mediated by the presence of androgens and subsequent mesenchyme-epithelial interactions. The investigation of prostate development is partly driven by its potential relevance to prostate cancer, in particular the apparent re-awakening of key developmental programs that occur during tumorigenesis. However, our current knowledge of the mechanisms that drive prostate organogenesis is far from complete. Here, we provide a comprehensive overview of prostate development, focusing on recent findings regarding sexual dimorphism, bud induction, branching morphogenesis and cellular differentiation. PMID:28400434

Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer.

PubMed

Breul, Jürgen; Lundström, Eija; Purcea, Daniela; Venetz, Werner P; Cabri, Patrick; Dutailly, Pascale; Goldfischer, Evan R

2017-02-01

Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9-8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

Impact of hormonal therapy on intermediate risk prostate cancer treated with combination brachytherapy and external beam irradiation.

PubMed

Stock, Richard G; Yalamanchi, Swati; Yamalachi, Swati; Hall, Simon J; Stone, Nelson N

2010-02-01

We assessed the impact of androgen suppressive therapy on biochemical failure in patients with intermediate risk prostate cancer treated with brachytherapy and external beam irradiation. From 1994 to 2006, 432 patients with intermediate risk prostate cancer as defined by the National Comprehensive Cancer Network were treated with low dose rate brachytherapy and external beam irradiation with or without 9 months of androgen suppressive therapy. Gleason score was 7 in 76% of cases and prostate specific antigen was 1.4 to 20 ng/ml (median 7.6). Of the patients 350 received androgen suppressive therapy and 82 did not. The biologically effective dose was 142 to 280 Gy2 (median 206). Followup was 23 to 155 months (median 56). The overall 8-year biochemical failure-free rate using the Phoenix definition in patients with vs without androgen suppressive therapy was 92% vs 92% (p = 0.4). The therapy had no significant impact on the biochemical failure-free rate in patients with Gleason score 7 (92% vs 90.5%, p = 0.55), prostate specific antigen 10 to 20 ng/ml (92% vs 100%, p = 0.32), T2b-T2c disease (89.5% vs 97%, p = 0.27) and more than 1 intermediate risk feature (90% vs 100%, p = 0.2). We addressed the relative importance of radiation dose vs hormonal therapy for intermediate risk prostate cancer. With high biologically effective dose combination treatment androgen suppressive therapy did not have a significant impact on the 8-year biochemical failure-free rate. We question its routine use in this setting. Copyright 2010 American Urological Association. Published by Elsevier Inc. All rights reserved.

Androgen-sensitive spermine-binding protein of rat ventral prostate. Purification of the protein and characterization of the hormonal effect.

PubMed Central

Mezzetti, G; Loor, R; Liao, S

1979-01-01

The rat ventral prostate contains a cytosol protein that can non-covalently bind spermine much more tightly than spermidine or other natural diamines. The protein has been purified to homogeneity, as judged by electrophoresis in urea- and sodium dodecyl sulphate-containing polyacrylamide gels. The protein, with or without spermine bound to it, sediments at 3 S in a sucrose gradient with or without 0.4 M-KCl. The molecular weight of the protein is about 30 000. Each molecule of the binding protein can bind one molecule of spermine. In the prostate of rats injected with cycloheximide, the protein appears to have a half-life of about 3.5 h. The spermine-binding activity of an acidic fraction obtained by DEAE-cellulose chromatography of the prostate cytosol proteins is reduced by about 40--60% within 20--40 h after castration. This effect is reversed very rapidly within 15--30 min by intraperitoneal injection of 5 alpha-dihydrotestosterone. The hormonal effect is androgen-specific and is not mimicked by dexamethasone or oestradiol-17 beta. The androgen effect was reduced significantly when rats were injected with cycloheximide or actinomycin D, suggesting that the acidic protein may be one of the earliest proteins induced by androgen in the rat ventral prostate. Images Fig. 1. PMID:534539

Do hormone treatments for prostate cancer cause anxiety and depression?

PubMed

Sharpley, Christopher F; Christie, David R H; Bitsika, Vicki

2014-01-01

To investigate the relationship between hormone therapy (HT) and incidence of anxiety and depression among prostate cancer patients (PCa). 526 PCa patients completed a survey about their cancer status, treatment received, anxiety, and depression status. Total scores on anxiety and depression inventories, plus symptom profiles that discriminated between patients with current HT, past HT, and never having received HT, were compiled for analysis. Patients who were currently receiving HT had significantly higher total anxiety and depression scores than patients who had previously received HT or who had never received HT. Analysis of the symptoms of anxiety and depression which distinguished between these groups of patients suggested that patients who had never received HT had significantly lower scores than current or past HT patients. Although several symptoms could be directly allocated to PCa and/or HT, symptom profiles were indicative of clinically significant anxiety and/or depression in patients who were currently receiving, or who had previously received, HT. Current HT may lead to symptoms of anxiety and/or depression which require clinical attention. These effects seem to decrease after completion of HT.

Decrease in the AgNOR number in Dunning R3327 prostate cancers after treatment with an agonist and antagonist of luteinizing hormone-releasing hormone.

PubMed Central

Szepeshazi, K.; Korkut, E.; Schally, A. V.

1991-01-01

The argyrophilic staining of the nucleolar organizer region (AgNOR) in cells of Dunning R3327 rat prostate tumors was studied and the effect of hormonal treatments on their appearance was analyzed. The nuclei of the control tumor cells contained 4.1 +/- 0.17 AgNOR granules. Treatment of rats for 8 weeks with luteinizing hormone-releasing hormone (LH-RH) agonist (D-Trp-6-LH-RH) and antagonist SB-75 induced a marked inhibition of tumor growth and decreased significantly (P less than 0.01) the number of Ag-NORs in the tumors to 2.89 +/- 0.10 AgNOR granules/cell in the group given the agonist and to 2.82 +/- 0.10 after therapy with the highest dose of the antagonist. A reduced AgNOR number (3.14 +/- 0.16) also was found after 3 days of treatment with SB-75 (P less than 0.05), but the AgNORs returned to near control values 1 week after the short-term therapy, showing the reversibility of these changes. These results suggest that the AgNOR method, which was widely tested on human tumors in the past few years, can be a valuable technique in experimental tumor pathology and useful in the evaluation of the effects of various treatments. Images Figure 1 PMID:1827237

Image analysis of androgen receptor immunostaining in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy.

PubMed

Sadi, M V; Barrack, E R

1993-04-15

Reliable predictors of the response of prostate cancer to androgen ablation therapy are lacking. The goals of this study were to determine whether nuclear androgen receptor (AR) concentrations in metastatic prostate cancer varied within and between specimens and to correlate this information with the response to therapy. AR concentration was evaluated by computer-assisted image analysis of immunohistochemical staining intensity in 200 malignant epithelial nuclei of each of 17 specimens of Stage D2 prostate cancer obtained before hormonal therapy. The data were correlated with the time to tumor progression (relapse) after hormonal therapy. AR staining intensity varied within specimens, and the variance of staining intensity was significantly greater (P = 0.03) in the poor responders (n = 8; time to progression, < 20 months) than in the good responders (n = 9; time to progression, > or = 20 months). The kurtosis was significantly lower in poor responders (P = 0.04). However, the mean AR staining intensity was not significantly different among patients. The frequency distribution plots of good responders were generally uniform and unimodal, but those of poor responders were flattened (more platykurtic), dispersed, and highly variable. Thus, the AR concentration per cell was significantly more heterogeneous in poor responders. Variance was a significant predictor of response. Five of 6 patients with a high variance (defined as variance greater than the mean) were poor responders, whereas 8 of 11 patients with a low variance were good responders (an overall classification accuracy of 13 of 17, 76%). The greater AR heterogeneity in poor responders may reflect a greater genetic instability in tumors that have progressed further toward androgen independence and may be a valuable predictor of progression.

The Role of the Urologist in Treating Patients with Hormone-Refractory Prostate Cancer

PubMed Central

Crawford, E. David

2003-01-01

Objectives: To ascertain what percentage of urologists’ oncology practice is dedicated to the care of prostate cancer patients and to determine urologists’ attitudes towards the treatment of patients with metastatic and hormone-refractory prostate cancer (HRPC). An additional objective is to determine urologists’ interest in administering various types of chemotherapy in HRPC patients. Materials and Methods: The American Urological Association (AUA) directory of practicing urologists was obtained, and 3000 randomly selected members of the AUA, as well as the complete list of 168 Society of Urologic Oncology (SUO) members, were chosen for the mailing of a 16-item questionnaire. The urologists were asked about how many of their patients have prostate cancer, how many have metastatic disease, and how many have HRPC and are currently receiving intravenous (IV) chemotherapy. In addition, the urologists were queried regarding their level of interest in learning about chemotherapy options as well as learning how to administer chemotherapy. Results: A total of 654 survey questionnaires were completed and returned for tabulation, resulting in a 21% effective response rate. Sixty-four percent of the responding urologists’ cancer patients had prostate cancer, 21% had metastatic disease, and 19% had HRPC; only 4% of the urologists currently administer IV chemotherapy themselves. When asked to describe their interest in learning how to deliver and be reimbursed for IV chemotherapy, 26% expressed an extremely low level of interest, 23% a low level of interest, 31% a high level of interest, and 17% an extremely high level of interest. The results of other questions are presented and correlated with the number of years the urologists have been in practice and other demographic data. Conclusions: The management of prostate cancer comprises a major portion of urologists’ practices. Almost one half (48%) of the urologists in this survey were interested in administering and

Depletion kinetics of circulating prostate cancer cells studied by in vivo flow cytometer

NASA Astrophysics Data System (ADS)

Liu, Guangda; Guo, Jin; Li, Yan; Chen, Yun; Gu, Zhengqin; Chen, Tong; Wang, Cheng; Wei, Xunbin

2010-11-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal nearinfrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

Breast and Prostate Cancer Cohort Consortium (BPC3)

Cancer.gov

Breast and Prostate Cancer Cohort Consortium collaborates with three genomic facilities, epidemiologists, population geneticists, and biostatisticians from multiple institutions to study hormone-related gene variants and environmental factors in breast and prostate cancers.

Active Sonic Hedgehog Signaling between Androgen Independent Human Prostate Cancer Cells and Normal/Benign but Not Cancer-Associated Prostate Stromal Cells

PubMed Central

Shigemura, Katsumi; Huang, Wen-Chin; Li, Xiangyan; Zhau, Haiyen E.; Zhu, Guodong; Gotoh, Akinobu; Fujisawa, Masato; Xie, Jingwu; Marshall, Fray F.; Chung, Leland W. K.

2012-01-01

BACKGROUND Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS CONCLUSIONS Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells. PMID:21520153

Bioengineering Multifunctional Quantum Dot-Polypeptide Assemblies and Immunoconjugates for the Ablation of Advanced Prostate Cancer Disease

DTIC Science & Technology

2008-02-01

disease [1]. Localized prostate cancer is generally treated with surgery (radical prostatectomy), radiation therapy, or cryotherapy [2]. However, disease...receiving radical radiotherapy were left with residual disease [3]. Currently, patients with recurrent, locally advanced, or metastatic prostate cancer are...treated by androgen deprivation alone or in combination with local therapy. Although most patients initially respond to androgen deprivation, a large

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

PubMed

Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

2012-02-01

Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

PubMed Central

O'Sullivan, J M; McCready, V R; Flux, G; Norman, A R; Buffa, F M; Chittenden, S; Guy, M; Pomeroy, K; Cook, G; Gadd, J; Treleaven, J; Al-Deen, A; Horwich, A; Huddart, R A; Dearnaley, D P

2002-01-01

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates. British Journal of Cancer (2002) 86, 1715–1720. doi:10.1038/sj.bjc.6600348 www.bjcancer.com © 2002 Cancer Research UK PMID:12087455

Formation of sex hormone transients resulting from attack of free radicals.

PubMed

Getoff, Nikola; Schittl, Heike; Gerschpacher, Marion; Quint, Ruth Maria

2013-03-01

Transients of the sex hormones testosterone (TES) and estrone (E1) exhibit an impact on the carcinogenesis of most prostate and breast cancer types. For elucidation of involved reaction mechanisms, in vitro, experiments using γ-ray for generation of attacking hormone transients and UV-light (λ=254 nm) for excitation of hormone molecules were applied. Materials and Methods. Experiments in vitro (Escherichia coli AB1157) incubated with TES and E1, individually as well as in mixture with vitamin C (electron donor), were performed under γ-irradiation in water-alcohol (40/60) medium for clarifying-up the reaction mechanism. The hormone degradation/regeneration processes were studied by high performance liquid chromatography analysis. Independently of hormone molecular structure, the determining factor for the biological properties, such as carcinogenity, were found to be based on the hormone transients. The biological ability of these, however, depends on the chemical properties of the species attacking the corresponding hormone. Hormone degradation can be, at least partly, converted into hormone regeneration by electron transfer from an electron donor (e.g. vitamin C), when available during the period of status nascendi of the hormone radicals.

Recommended patient-reported core set of symptoms to measure in prostate cancer treatment trials.

PubMed

Chen, Ronald C; Chang, Peter; Vetter, Richard J; Lukka, Himansu; Stokes, William A; Sanda, Martin G; Watkins-Bruner, Deborah; Reeve, Bryce B; Sandler, Howard M

2014-07-01

The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee convened four working groups to recommend core sets of patient-reported outcomes to be routinely incorporated in clinical trials. The Prostate Cancer Working Group included physicians, researchers, and a patient advocate. The group's process included 1) a systematic literature review to determine the prevalence and severity of symptoms, 2) a multistakeholder meeting sponsored by the NCI to review the evidence and build consensus, and 3) a postmeeting expert panel synthesis of findings to finalize recommendations. Five domains were recommended for localized prostate cancer: urinary incontinence, urinary obstruction and irritation, bowel-related symptoms, sexual dysfunction, and hormonal symptoms. Four domains were recommended for advanced prostate cancer: pain, fatigue, mental well-being, and physical well-being. Additional domains for consideration include decisional regret, satisfaction with care, and anxiety related to prostate cancer. These recommendations have been endorsed by the NCI for implementation. © The Author 2014. Published by Oxford University Press. All rights reserved.

Regional hyperthermia in conjunction with definitive radiotherapy against recurrent or locally advanced prostate cancer T3 pN0 M0.

PubMed

Tilly, Wolfgang; Gellermann, Johanna; Graf, Reinhold; Hildebrandt, Bert; Weissbach, Lothar; Budach, Volker; Felix, Roland; Wust, Peter

2005-01-01

Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study. From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters. Mean maximum temperatures along the urethra of 41.4 degrees C (41.0 degrees C for the recurrences), and mean T(90) values of 40.7 degrees C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control. Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.

METastasis Reporting and Data System for Prostate Cancer: Practical Guidelines for Acquisition, Interpretation, and Reporting of Whole-body Magnetic Resonance Imaging-based Evaluations of Multiorgan Involvement in Advanced Prostate Cancer.

PubMed

Padhani, Anwar R; Lecouvet, Frederic E; Tunariu, Nina; Koh, Dow-Mu; De Keyzer, Frederik; Collins, David J; Sala, Evis; Schlemmer, Heinz Peter; Petralia, Giuseppe; Vargas, H Alberto; Fanti, Stefano; Tombal, H Bertrand; de Bono, Johann

2017-01-01

Comparative reviews of whole-body magnetic resonance imaging (WB-MRI) and positron emission tomography/computed tomography (CT; with different radiotracers) have shown that metastasis detection in advanced cancers is more accurate than with currently used CT and bone scans. However, the ability of WB-MRI and positron emission tomography/CT to assess therapeutic benefits has not been comprehensively evaluated. There is also considerable variability in the availability and quality of WB-MRI, which is an impediment to clinical development. Expert recommendations for standardising WB-MRI scans are needed, in order to assess its performance in advanced prostate cancer (APC) clinical trials. To design recommendations that promote standardisation and diminish variations in the acquisition, interpretation, and reporting of WB-MRI scans for use in APC. An international expert panel of oncologic imagers and oncologists with clinical and research interests in APC management assessed biomarker requirements for clinical care and clinical trials. Key requirements for a workable WB-MRI protocol, achievable quality standards, and interpretation criteria were identified and synthesised in a white paper. The METastasis Reporting and Data System for Prostate Cancer guidelines were formulated for use in all oncologic manifestations of APC. Uniformity in imaging data acquisition, quality, and interpretation of WB-MRI are essential for assessing the test performance of WB-MRI. The METastasis Reporting and Data System for Prostate Cancer standard requires validation in clinical trials of treatment approaches in APC. METastasis Reporting and Data System for Prostate Cancer represents the consensus recommendations on the performance, quality standards, and reporting of whole-body magnetic resonance imaging, for use in all oncologic manifestations of advanced prostate cancer. These new criteria require validation in clinical trials of established and new treatment approaches in advanced

Evidence of prostate cancer "reverse stage migration" toward more advanced disease at diagnosis: Data from the Pennsylvania Cancer Registry.

PubMed

Reese, Adam C; Wessel, Sean R; Fisher, Susan G; Mydlo, Jack H

2016-08-01

The widespread adoption of prostate-specific antigen-based prostate cancer screening caused a stage migration toward earlier stage disease at diagnosis. We investigated whether this stage migration has persisted in a contemporary analysis of a population-based statewide cancer registry. We analyzed the Pennsylvania Cancer Registry, a statewide registry of all newly diagnosed cancers. Data were collected on prostate cancers diagnosed between 1992 and 2012. We determined age-adjusted prostate cancer incidence and mortality rates, as well as the distribution of tumor stage (localized, regional, or metastatic) at diagnosis, and assessed for changes in these variables over time using joinpoint analysis. Between 1992 and 2012, 210,831 new cases of prostate cancer were diagnosed in Pennsylvania, and 33,948 men died of disease. Age-adjusted prostate cancer incidence rates, and specifically the incidence of localized disease, have decreased dramatically since 2007 to 2008. Due to the decreased diagnosis of localized disease, regional and metastatic tumors have made up a greater percentage of all prostate cancer diagnoses in recent years, despite a relatively stable incidence of these advanced stage tumors. Over the past 2 decades, age-adjusted prostate cancer incidence rates in Pennsylvania have decreased, primarily because of the decreased detection of early-stage disease. There has been a corresponding shift toward more advanced disease at diagnosis. These findings may be explained by the decreased use of prostate-specific antigen-based screening, among other factors. The 2012 United States Preventative Services Task Force recommendations against prostate cancer screening may exacerbate this concerning trend, potentially resulting in an increase in prostate cancer-specific mortality. Copyright © 2016 Elsevier Inc. All rights reserved.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-01-01

Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

PubMed

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-03-19

Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with

Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals.

PubMed

Collette, Laurence; Burzykowski, Tomasz; Carroll, Kevin J; Newling, Don; Morris, Tom; Schröder, Fritz H

2005-09-01

The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa. Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered. The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69). It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) in Patients with Hormone-Refractory Metastatic Prostate Cancer

PubMed Central

Heath, Elisabeth I.; Hillman, David W.; Vaishampayan, Ulka; Sheng, Shijie; Sarkar, Fazlul; Harper, Felicity; Gaskins, Melvin; Pitot, Henry C.; Tan, Winston; Ivy, S. Percy; Pili, Roberto; Carducci, Michael A.; Liu, Glenn

2011-01-01

Purpose 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with anti-proliferative activity in several mouse xenograft models including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Experimental Design Patients with at least one prior systemic therapy and a rising PSA were eligible. Patients received 17-AAG at a dose of 300 mg/m2 IV weekly for three out of four weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, to measure IL-6, IL-8 and maspin levels and quality of life. Results Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of 2 cycles. Severe adverse events included: grade 3 fatigue (4 pts), grade 3 lymphopenia (2 pts) and grade 3 back pain (2 pts). The median PSA progression free survival was 1.8 months (95% CI: 1.3–3.4 months). The six-month overall survival was 71% (95% CI: 52%–100%). Conclusion 17-AAG did not show any activity with regards to PSA response. Due to insufficient PSA response, enrollment was stopped at end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 IV weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted. PMID:19047126

A Changing Landscape of Advanced Prostate Cancer: Understanding Mechanisms of Resistance to Potent Hormonal Therapies

DTIC Science & Technology

2016-10-01

are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other...NEPC) phenotype has emerged as an important mechanism of treatment resistance to androgen receptor ( AR ) therapies for patients with metastatic prostate...for emergence of NEPC CTC characteristics and found that up to 10% harbor NEPC-like CTCs (characterized by low AR , smaller morphology, loss of CK), and

CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor–Positive Advanced Breast Cancer?

PubMed

Shah, Mirat; Nunes, Maria Raquel; Stearns, Vered

2018-05-15

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are rapidly transforming the care of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer. Current clinical questions include how to choose among these agents and how to sequence them with other therapies. Areas of active inquiry include identifying predictive biomarkers for CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression, creating novel treatment combinations, and expanding use beyond HR+/HER2- advanced breast cancer. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+ breast cancer.

Final report on low-dose estramustine phosphate (EMP) monotherapy and very low-dose EMP therapy combined with LH-RH agonist for previously untreated advanced prostate cancer.

PubMed

Kitamura, T; Suzuki, M; Nishimatsu, H; Kurosaki, T; Enomoto, Y; Fukuhara, H; Kume, H; Takeuchi, T; Miao, L; Jiangang, H; Xiaoqiang, L

2010-01-01

In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups. Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2. Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2. Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of

Adoptive cell therapy of prostate cancer using female mice-derived T cells that react with prostate antigens

PubMed Central

Yi, Huanfa; Yu, Xiaofei; Guo, Chunqing; Manjili, Masoud H.; Repasky, Elizabeth A.; Wang, Xiang-Yang

2011-01-01

In this study, we report a novel treatment strategy that could potentially be used to improve efficacy of adoptive cell therapy for patients with prostate cancer. We show that female C57BL/6 mice are able to effectively reject two syngeneic prostate tumors (TRAMP-C2 and RM1) in a T cell-dependent manner. The protective antitumor immunity appears to primarily involve T cell responses reactive against general prostate tumor/tissue antigens, rather than simply to male-specific H-Y antigen. For the first time we show that adoptive transfer of lymphocytes from TRAMP-C2-primed or naive female mice effectively control prostate tumor growth in male mice, when combined with host pre-conditioning (i.e., non-myeloablative lymphodepletion) and IL-2 administration. No pathological autoimmune response was observed in the treated tumor-bearing male mice. Our studies provide new insights regarding the immune-mediated recognition of male-specific tissue, such as the prostate, and may offer new immunotherapy treatment strategies for advanced prostate cancer. PMID:21088965

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

PubMed Central

Dasgupta, Subhamoy; Putluri, Nagireddy; Long, Weiwen; Zhang, Bin; Wang, Jianghua; Kaushik, Akash K.; Arnold, James M.; Bhowmik, Salil K.; Stashi, Erin; Brennan, Christine A.; Rajapakshe, Kimal; Coarfa, Cristian; Mitsiades, Nicholas; Ittmann, Michael M.; Chinnaiyan, Arul M.; Sreekumar, Arun; O’Malley, Bert W.

2015-01-01

Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2–driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer. PMID:25664849

Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer.

PubMed

Soekmadji, Carolina; Corcoran, Niall M; Oleinikova, Irina; Jovanovic, Lidija; Ramm, Grant A; Nelson, Colleen C; Jenster, Guido; Russell, Pamela J

2017-10-01

The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation. © 2017 Wiley Periodicals, Inc.

Studying depletion kinetics of circulating prostate cancer cells by in vivo flow cytometer

NASA Astrophysics Data System (ADS)

Liu, Guangda; Gu, Zhengqin; Guo, Jin; Li, Yan; Chen, Yun; Chen, Tong; Wang, Cheng; Wei, Xunbin

2011-03-01

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. The tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs. As the cancer advances, however, it can metastasize throughout other areas of the body, such as the bones, lungs, and liver. Surgical resection, hormonal therapy, chemotherapy and radiation therapy are the foundation of current prostate cancer therapies. Treatments for prostate cause both short- and long-term side effects that may be difficult to accept. Molecular mechanisms of prostate cancer metastasis need to be understood better and new therapies must be developed to selectively target to unique characteristics of cancer cell growth and metastasis. We have developed the "in vivo microscopy" to study the mechanisms that govern prostate cancer cell spread through the microenvironment in vivo in real-time confocal near-infrared fluorescence imaging. A recently developed "in vivo flow cytometer" and optical imaging are used to assess prostate cancer cell spreading and the circulation kinetics of prostate cancer cells. A real- time quantitative monitoring of circulating prostate cancer cells by the in vivo flow cytometer will be useful to assess the effectiveness of the potential therapeutic interventions.

[Endocrine disruptors, reproduction and hormone-dependent cancers].

PubMed

Fenichel, Patrick; Brucker-Davis, Françoise; Chevalier, Nicolas

2016-01-01

Endocrine disruptors are natural or synthetic chemical compounds which are present in the environment and which are able to interfere with hormonal regulation pathways and to induce human health deleterious effects. While their precise implication in human health and diseases is still matter of debates, it becomes likely that they have to be considered as risk factors in numerous chronic diseases: developmental and reproductive defects and hormone dependent cancers (present review), metabolic diseases (obesity and type 2 diabetes), neurodevelopmental or neurodegenerative diseases. Low doses exposure during critical windows of exposure such as foetal, perinatal and peri-pubertal periods, or chronic exposure with bioaccumulation in the adipose tissue, and possible synergic effects of several compounds ("cocktail effect") may participate to the genetic/environment interface suspected to participate to the pathophysiology of many diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Mindfulness-Based Cognitive Therapy in Advanced Prostate Cancer: A Randomized Controlled Trial.

PubMed

Chambers, Suzanne K; Occhipinti, Stefano; Foley, Elizabeth; Clutton, Samantha; Legg, Melissa; Berry, Martin; Stockler, Martin R; Frydenberg, Mark; Gardiner, Robert A; Lepore, Stephen J; Davis, Ian D; Smith, David P

2017-01-20

Purpose Advanced prostate cancer (PC) is associated with substantial psychosocial morbidity. We sought to determine whether mindfulness-based cognitive therapy (MBCT) reduces distress in men with advanced PC. Methods Men with advanced PC (proven metastatic and/or castration-resistant biochemical progression) were randomly assigned to an 8-week, group-based MBCT intervention delivered by telephone (n = 94) or to minimally enhanced usual care (n = 95). Primary intervention outcomes were psychological distress, cancer-specific distress, and prostate-specific antigen anxiety. Mindfulness skills were assessed as potential mediators of effect. Participants were assessed at baseline and were followed up at 3, 6, and 9 months. Main statistical analyses were conducted on the basis of intention to treat. Results Fourteen MBCT groups were conducted in the intervention arm. Facilitator adherence ratings were high (> 93%). Using random-effects mixed-regression models, intention-to-treat analyses indicated no significant changes in intervention outcomes or in engagement with mindfulness for men in MBCT compared with those receiving minimally enhanced usual care. Per-protocol analyses also found no differences between arms in outcomes or engagement, with the exception of the mindfulness skill of observing, which increased over time for men in MBCT compared with usual care ( P = .032). Conclusion MBCT in this format was not more effective than minimally enhanced usual care in reducing distress in men with advanced PC. Future intervention research for these men should consider approaches that map more closely to masculinity.

Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3

DTIC Science & Technology

2010-05-10

target of rapamycin ( mTOR ) and hypoxia-inducible factor-1α (HIF-1α) target genes (12). Additionally, transcriptional activation of Bcl-2 by NF-κB...in resistance to hormone therapy (19). Elevated expression of genes encoding PI3K/Akt/ mTOR pathway components has also been implicated in androgen... mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med, 10

Positive and negative mood in men with advanced prostate cancer undergoing androgen deprivation therapy: considering the role of social support and stress.

PubMed

Benedict, Catherine; Dahn, Jason R; Antoni, Michael H; Traeger, Lara; Kava, Bruce; Bustillo, Natalie; Zhou, Eric S; Penedo, Frank J

2015-08-01

Advanced prostate cancer patients often undergo androgen deprivation therapy (ADT). Advanced disease and adverse ADT side effects are often debilitating and negatively impact mood. Social support has been shown to mitigate detrimental effects of stress on mood. This study sought to characterize positive and negative mood in this select patient population and determine whether social support moderated relations between stress and mood. Participants (N = 80) completed the Interpersonal Support Evaluation List, Perceived Stress Scale, and Derogatis Affect Balance Scale at a single time point. Hierarchical regression models evaluated relations among social support, stress, and mood controlling for relevant covariates. Standard moderation analyses were performed. Participants reported higher levels of negative and positive mood compared with published means of localized prostate cancer patients. Overall, mood was more positive than negative. Stress levels were comparable to cancer populations with recurrent disease. Moderated regression analyses showed that social support partially buffered the effects of stress on positive mood; men with high stress and low support reported the lowest levels of positive mood. The model with negative mood as the dependent measure did not support moderation; that is, the relationship between stress and negative mood did not differ by level of social support. Among individuals living with advanced prostate cancer, social support may be an important factor that sustains positive mood in the presence of stress. Future work should examine the extent to which social support prospectively impacts health-related quality of life by promoting positive mood. Limitations include cross-sectional design, which precludes causal inferences. Copyright © 2014 John Wiley & Sons, Ltd.

Sphingosine Kinase-1 Is Central to Androgen-Regulated Prostate Cancer Growth and Survival

PubMed Central

Dayon, Audrey; Brizuela, Leyre; Martin, Claire; Mazerolles, Catherine; Pirot, Nelly; Doumerc, Nicolas; Nogueira, Leonor; Golzio, Muriel; Teissié, Justin; Serre, Guy; Rischmann, Pascal; Malavaud, Bernard; Cuvillier, Olivier

2009-01-01

Background Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. Methodology/Principal Findings Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway—by negatively impacting SphK1 activity—could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. Conclusions/Significance We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a compensatory mechanism

High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines.

PubMed

Chowdhury, Subir K R; Gemin, Adam; Singh, Gurmit

2005-08-12

Most malignant cells are highly glycolytic and produce high levels of reactive oxygen species (ROS) compared to normal cells. Mitochondrial glycerophosphate dehydrogenase (mGPDH) participates in the reoxidation of cytosolic NADH by delivering reducing equivalents from this molecule into the electron transport chain, thus sustaining glycolysis. Here, we investigate the role of mGPDH in maintaining an increased rate of glycolysis and evaluate glycerophosphate-dependent ROS production in prostate cancer cell lines (LNCaP, DU145, PC3, and CL1). Immunoblot, polarographic, and spectrophotometric analyses revealed that mGPDH abundance and activity was significantly elevated in prostate cancer cell lines when compared to the normal prostate epithelial cell line PNT1A. Furthermore, both the glycolytic capacity and glycerophosphate-dependent ROS production was increased 1.68- to 4.44-fold and 5- to 7-fold, respectively, in prostate cancer cell lines when compared to PNT1A cells. Overall, these data demonstrate that mGPDH is involved in maintaining a high rate of glycolysis and is an important site of electron leakage leading to ROS production in prostate cancer cells.

Targeting monoamine oxidase A in advanced prostate cancer.

PubMed

Flamand, Vincent; Zhao, Hongjuan; Peehl, Donna M

2010-11-01

Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA. Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction. Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro. Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women.

PubMed

Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E

2017-05-01

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society

Androgen deprivation therapy for prostate cancer: long-term safety and patient outcomes

PubMed Central

Ahmadi, Hamed; Daneshmand, Siamak

2014-01-01

Androgen deprivation therapy (ADT) constitutes the first-line treatment for patients with locally advanced tumors, recurrent or metastatic disease. Given its widespread use, clinicians should be familiar with common side effects of this treatment. This review focuses on common side effects of ADT and available treatment options to control the side effects. Also, it briefly compares continuous ADT with other therapeutic approaches for androgen deprivation in prostate cancer patients. Similar to hormonal medications, newer non-hormonal therapeutic options including gabapentin and acupuncture have at best moderate effect in controlling hot flashes in patients on ADT. Supervised and/or home exercise programs significantly improve ADT-related fatigue, metabolic/cardiovascular side effects, and cognitive dysfunction. Denosumab, a human monoclonal antibody against RANK-L, is more effective than bisphosphonates in preventing skeletal-related events in patients with metastatic or castrate-resistant prostate cancer and unlike bisphosphonates, it can also reduce the risk of vertebral fractures in men receiving ADT for non-metastatic prostate cancer. Toremifene, a selective estrogen receptor inhibitor, has dual beneficial effects on ADT-related osteoporosis and metabolic dysfunction. Metformin coupled with lifestyle modification is also a well-tolerated treatment for metabolic changes during ADT. While producing similar oncological outcomes, intermittent ADT is associated with higher quality of life in patients under ADT by improving bone health, less metabolic and hematologic complications, and fewer hot flashes and sexual dysfunction events. PMID:25045284

Establishment of prostate cancer spheres from a prostate cancer cell line after phenethyl isothiocyanate treatment and discovery of androgen-dependent reversible differentiation between sphere and neuroendocrine cells.

PubMed

Chen, Yamei; Cang, Shundong; Han, Liying; Liu, Christina; Yang, Patrick; Solangi, Zeeshan; Lu, Quanyi; Liu, Delong; Chiao, J W

2016-05-03

Prostate cancer can transform from androgen-responsive to an androgen-independent phenotype. The mechanism responsible for the transformation remains unclear. We studied the effects of an epigenetic modulator, phenethyl isothiocyanate (PEITC), on the androgen-responsive LNCaP cells. After treatment with PEITC, floating spheres were formed with characteristics of prostate cancer stem cells (PCSC). These spheres were capable of self-renewal in media with and without androgen. They have been maintained in both types of media as long term cultures. Upon androgen deprivation, the adherent spheres differentiated to neuroendocrine cells (NEC) with decreased proliferation, expression of androgen receptor, and PSA. NEC reverse differentiated to spheres when androgen was replenished. The sphere cells expressed surface marker CD44 and had enhanced histone H3K4 acetylation, DNMT1 down-regulation and GSTP1 activation. We hypothesize that PEITC-mediated alteration in epigenomics of LNCaP cells may give rise to sphere cells, whereas reversible androgenomic alterations govern the shuttling between sphere PCSC and progeny NEC. Our findings identify unrecognized properties of prostate cancer sphere cells with multi-potential plasticity. This system will facilitate development of novel therapeutic agents and allow further exploration into epigenomics and androgenomics governing the transformation to hormone refractory prostate cancer.

[Epigenetics of prostate cancer].

PubMed

Yi, Xiao-Ming; Zhou, Wen-Quan

2010-07-01

Prostate cancer is one of the most common malignant tumors in males, and its etiology and pathogenesis remain unclear. Epigenesis is involved in prostate cancer at all stages of the process, and closely related with its growth and metastasis. DNA methylation and histone modification are the most important manifestations of epigenetics in prostate cancer. The mechanisms of carcinogenesis of DNA methylation include whole-genome hypomethylation, aberrant local hypermethylation of promoters and genomic instability. DNA methylation is closely related to the process of prostate cancer, as in DNA damage repair, hormone response, tumor cell invasion/metastasis, cell cycle regulation, and so on. Histone modification causes corresponding changes in chromosome structure and the level of gene transcription, and it may affect the cycle, differentiation and apoptosis of cells, resulting in prostate cancer. Some therapies have been developed targeting the epigenetic changes in prostate cancer, including DNA methyltransferases and histone deacetylase inhibitors, and have achieved certain desirable results.

Radiation Therapy Did Not Induce Long-Term Changes in Rectal Mucosa: Results From the Randomized Scandinavian Prostate Cancer Group 7 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slagsvold, Jens Erik, E-mail: Jens.Erik.Slagsvold@stolav.no; Viset, Trond; Wibe, Arne

Purpose: To investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer. Methods and Materials: In the Scandinavian Prostate Cancer Group 7 trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70 Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5 years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analyticmore » (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies were included in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy. Results: The group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups. Conclusion: Radiation therapy to 70 Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5 years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa.« less

Selinexor in Treating Patients With Abiraterone Acetate and/or Enzalutamide Refractory Metastatic Castration-Resistant Prostate Cancer

ClinicalTrials.gov

2018-05-29

Castration Levels of Testosterone; Hormone-Resistant Prostate Cancer; Metastatic Prostate Carcinoma in the Soft Tissue; Prostate Carcinoma Metastatic in the Bone; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Corn silk maysin induces apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway.

PubMed

Lee, Jisun; Lee, Seul; Kim, Sun-Lim; Choi, Ji Won; Seo, Jeong Yeon; Choi, Doo Jin; Park, Yong Il

2014-12-05

Despite recent advances in prostate cancer diagnostics and therapeutics, the overall survival rate still remains low. This study was aimed to assess potential anti-cancer activity of maysin, a major flavonoid of corn silk (CS, Zea mays L.), in androgen-independent human prostate cancer cells (PC-3). Maysin was isolated from CS of Kwangpyeongok, a Korean hybrid corn, via methanol extraction and preparative C18 reverse phase column chromatography. Maysin cytotoxicity was determined by either monitoring cell viability in various cancer cell lines by MTT assay or morphological changes. Apoptotic cell death was assessed by annexin V-FITC/PI double staining, depolarization of mitochondrial membrane potential (MMP), expression levels of Bcl-2 and pro-caspase-3 and by terminal transferase mediated dUTP-fluorescein nick end labeling (TUNEL) staining. Underlying mechanism in maysin-induced apoptosis of PC-3 cells was explored by evaluating its effects on Akt and ERK pathway. Maysin dose-dependently reduced the PC-3 cell viability, with an 87% reduction at 200 μg/ml. Maysin treatment significantly induced apoptotic cell death, DNA fragmentation, depolarization of MMP, and reduction in Bcl-2 and pro-caspase-3 expression levels. Maysin also significantly attenuated phosphorylation of Akt and ERK. A combined treatment with maysin and other known anti-cancer agents, including 5-FU, etoposide, cisplatin, or camptothecin, synergistically enhanced PC-3 cell death. These results suggested for the first time that maysin inhibits the PC-3 cancer cell growth via stimulation of mitochondria-dependent apoptotic cell death and may have a strong therapeutic potential for the treatment of either chemo-resistant or androgen-independent human prostate cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Circadian and sleep-dependent regulation of hormone release in humans

NASA Technical Reports Server (NTRS)

Czeisler, C. A.; Klerman, E. B.

1999-01-01

Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian

Risks, benefits, and approaches to hormonal blockade in prostate cancer. Highlights from the European Association of Urology Meeting, March 20-24, 2015, Madrid, Spain.

PubMed

Barkin, Jack

2015-06-01

Several abstracts presented at the 2015 European Association of Urology Meeting highlighted new developments in hormone therapy for prostate cancer management. One abstract described how the luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) agonist leuprolide, but not the LHRH/GnRH antagonist degarelix, induced plaque instability in a mouse model. A second abstract showed that in patients with a history of severe cardiovascular disease, degarelix was associated with fewer cardiovascular events than treatment with an LHRH agonist. A third abstract showed how primary androgen-deprivation therapy was linked with increased all-cause mortality in a US registry. A fourth abstract showed that in the ANAMEN study, cognitive performance was not significantly affected by 6 months of treatment with GnRH agonists. Last, a fifth abstract showed that low-dose prednisone, with or without abiraterone, was associated with an overall low incidence of corticosteroid-associated adverse events.

STEAP: A prostate-specific cell-surface antigen highly expressed in human prostate tumors

PubMed Central

Hubert, Rene S.; Vivanco, Igor; Chen, Emily; Rastegar, Shiva; Leong, Kahan; Mitchell, Steve C.; Madraswala, Rashida; Zhou, Yanhong; Kuo, James; Raitano, Arthur B.; Jakobovits, Aya; Saffran, Douglas C.; Afar, Daniel E. H.

1999-01-01

In search of novel genes expressed in metastatic prostate cancer, we subtracted cDNA isolated from benign prostatic hypertrophic tissue from cDNA isolated from a prostate cancer xenograft model that mimics advanced disease. One novel gene that is highly expressed in advanced prostate cancer encodes a 339-amino acid protein with six potential membrane-spanning regions flanked by hydrophilic amino- and carboxyl-terminal domains. This structure suggests a potential function as a channel or transporter protein. This gene, named STEAP for six-transmembrane epithelial antigen of the prostate, is expressed predominantly in human prostate tissue and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. Immunohistochemical analysis of clinical specimens demonstrates significant STEAP expression at the cell–cell junctions of the secretory epithelium of prostate and prostate cancer cells. Little to no staining was detected at the plasma membranes of normal, nonprostate human tissues, except for bladder tissue, which expressed low levels of STEAP at the cell membrane. Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. Our results support STEAP as a cell-surface tumor-antigen target for prostate cancer therapy and diagnostic imaging. PMID:10588738

Decreased immunostaining for macrophage scavenger receptor is associated with poor prognosis of prostate cancer.

PubMed

Takayama, Hitoshi; Nonomura, Norio; Nishimura, Kazuo; Oka, Daizo; Shiba, Masahiro; Nakai, Yasutomo; Nakayama, Masashi; Tsujimura, Akira; Aozasa, Katsuyuki; Okuyama, Akihiko

2009-02-01

The aim of this study is to evaluate the expression of the macrophage scavenger receptor (MSR) in prostate needle biopsy specimens as a possible prognostic factor for prostate cancer. As MSR reportedly has a role in recognizing foreign pathogenic substances, MSR-positive inflammatory cells are often detected in solid tumours, and there is a correlation between the relative risk of prostate cancer and polymorphism of the MSR gene. MSR was evaluated by immunostaining in needle biopsies of the prostate from 135 patients who were confirmed to have prostate cancer. Among these men, 70 were treated by radical prostatectomy or by radiotherapy as definitive therapy; the other 65 were treated by hormonal therapy because of advanced disease or age. Needle-biopsy specimens were sectioned at 5 microm and immunostained with a monoclonal antibody against MSR. Six microscopic (x400) fields around the cancer foci were selected in each case for analysis. The median number of MSR-positive cells (MSR count) in each case was 24. There was an inverse correlation between the MSR count and Gleason score and clinical stage. The MSR count was lower in patients with biochemical (prostate-specific antigen, PSA) failure than that in those with no PSA failure (P < 0.001). In all patients, the recurrence-free survival (RFS) rate was significantly higher in those with a high MSR count (> or =24) than that in those with low MSR count (<24, P < 0.001). Moreover, for patients treated by definitive or hormonal therapy, the RFS rates in those with a higher MSR count were higher than in those with a lower MSR count (P < 0.001 and 0.014, respectively). Cox multivariate analysis showed that the MSR count was a prognostic factor for prostate cancer in addition to extraprostatic extension and Gleason score (P = 0.002, 0.038 and 0.011, respectively). The results of immunostaining of MSR in needle-biopsy specimens is a prognostic factor for prostate cancer.

A single-chain fragment against prostate specific membrane antigen as a tool to build theranostic reagents for prostate cancer.

PubMed

Frigerio, B; Fracasso, G; Luison, E; Cingarlini, S; Mortarino, M; Coliva, A; Seregni, E; Bombardieri, E; Zuccolotto, G; Rosato, A; Colombatti, M; Canevari, S; Figini, M

2013-06-01

Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers. Published by Elsevier Ltd.

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

PubMed

Xie, Jipan; Namjoshi, Madhav; Wu, Eric Q; Parikh, Kejal; Diener, Melissa; Yu, Andrew P; Guo, Amy; Culver, Kenneth W

2011-10-01

Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first

Successful desensitization to Gonadotropin-releasing hormone analogue Triptorelin Acetate using a sustained-release depot preparation.

PubMed

Chan Ng, Pauline; Huang, Chiung-Hui; Rajakulendran, Mohana; Tan, Michelle Meiling; Wang, Ping Ping; Tay, Lei Qiu; Goh, Siok Ying; Shek, Lynette Pei-Chi; Tham, Elizabeth Huiwen

2018-05-29

Gonadotropin-releasing hormone (GnRH) analogues are commonly used in pediatric patients in the treatment of central precocious puberty 1 . GnRH analogues suppress the secretion of gonadotropins and sex hormones, preventing progression to advanced puberty and reduced final adult height secondary to accelerated fusion of growth plates. GnRH analogues are also used in adults for treatment of endometriosis 2 and prostatic cancer 3 . Hypersensitivity reactions to GnRH analogues are exceedingly rare 4-6 and to date, we are unaware of any desensitization protocols for GnRH hypersensitivity in the literature or used in clinical practice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prostate cancer risk: the significance of differences in age related changes in serum conjugated and unconjugated steroid hormone concentrations between Arab and Caucasian men.

PubMed

Kehinde, E O; Akanji, A O; Memon, A; Bashir, A A; Daar, A S; Al-Awadi, K A; Fatinikun, T

2006-01-01

Factors responsible for the low incidence of clinical prostate cancer (3-8/100,000 men/year) in the Arab population remain unclear, but may be related to changes in steroid hormone metabolism. We compared the levels of serum conjugated and unconjugated steroids between Arab and Caucasian populations, to determine if these can provide a rational explanation for differences in incidence of prostate cancer between the two populations. Venous blood samples were obtained from 329 unselected apparently healthy indigenous Arab men (Kuwaitis and Omanis) aged 15-80 years. Samples were also obtained from similar Arab men with newly diagnosed prostate cancer or benign prostatic hyperplasia (BPH). The samples were taken between 8:00 am and 12:00 noon. Serum levels of total testosterone, (TT), sex hormone binding globulin (SHBG), free androgen index (FAI); adrenal C19-steroids, dehydroepiandrosterone sulphate (DHEAS) and androstenedione (ADT) were determined using Immulite kits (Diagnostic Systems Laboratories Inc, Webster Texas, USA). The results obtained in Arab men were compared with those reported for similarly aged Chinese, German and White USA men. In all four ethnic groups, median TT and FAI declined with age, while SHBG increased with age. However, the mean TT and SHBG was significantly lower (p < 0.01) and the FAI significantly higher in Arab men (p < 0.01) compared to German men only in 21-30 years age group. In the other age groups the levels of TT and SHBG were higher in the Germans but the differences were not statistically significant. In all the racial groups serum levels of DHEAS and ADT reached a peak by about 20 years of life, and then declined progressively. The mean DHEAS in American Caucasians aged 20-29 years was 11.4 micromol/l compared to 6.22 micromol/l in the Arabs (p < 0.001). The mean DHEAS in USA Caucasians aged 70-79 years was 2.5 micromol/l compared to 1.8 micromol/l (p < 0.03) in the Arabs. There was no significant difference in mean serum levels

The biology and natural history of prostate cancer: a short introduction.

PubMed

Holmberg, Lars; Van Hemelrijck, Mieke

2014-01-01

This chapter aims to serve as a quick glance outlining an overall picture of mainstream thoughts, and to serve as a point of departure for more thorough discussions. The introduction of PSA testing has immensely complicated research in prostate cancer epidemiology and biology and added new clinical and biological domains. As for many cancers, age and ethnic origin are the strongest known risk factors. While migrant studies imply that environment and/or personal life style is important, epidemiological studies have failed to establish any strong leads. Despite the known androgen dependence of prostate cancer, there is little to support that circulating levels of androgens, estrogens or 5-alpha-reductase are associated with risk of developing the disease. However, a consistent finding is a positive association with levels of Insulin-like Growth Factor-1 (IGF-1). Prostate cancer is one of the cancers most strongly related to inherited susceptibility, even when taking into account that family history of prostate cancer triggers PSA testing among relatives. A number of somatic genetic alterations (amplifications, deletions, point mutations, translocations) are associated with prostate cancer risk. Findings for alterations in FASN, HPN, AMACR and MYC have been fairly consistent. Recent research shows that the notion of "hormone-independent prostate cancer" has to be revised: most prostate cancers remain dependent on androgen receptor signalling also after progression despite traditional androgen deprivation therapy. Traditional markers of stage and type of disease still play a major role for prognostication and treatment decisions. Prostate cancer is one of the few cancers where patients have been recommended watchful waiting or active surveillance. This provides opportunities for studies of natural history of the disease. The understanding of prostate cancer aetiology and natural history has progressed slowly. However, the current situation is positively challenging and

High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chowdhury, Subir K.R.; Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Hamilton, Ont., L8N 3Z5; Gemin, Adam

Most malignant cells are highly glycolytic and produce high levels of reactive oxygen species (ROS) compared to normal cells. Mitochondrial glycerophosphate dehydrogenase (mGPDH) participates in the reoxidation of cytosolic NADH by delivering reducing equivalents from this molecule into the electron transport chain, thus sustaining glycolysis. Here, we investigate the role of mGPDH in maintaining an increased rate of glycolysis and evaluate glycerophosphate-dependent ROS production in prostate cancer cell lines (LNCaP, DU145, PC3, and CL1). Immunoblot, polarographic, and spectrophotometric analyses revealed that mGPDH abundance and activity was significantly elevated in prostate cancer cell lines when compared to the normal prostate epithelialmore » cell line PNT1A. Furthermore, both the glycolytic capacity and glycerophosphate-dependent ROS production was increased 1.68- to 4.44-fold and 5- to 7-fold, respectively, in prostate cancer cell lines when compared to PNT1A cells. Overall, these data demonstrate that mGPDH is involved in maintaining a high rate of glycolysis and is an important site of electron leakage leading to ROS production in prostate cancer cells.« less

A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

PubMed

Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

2016-10-01

The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT

Association of Androgen Metabolism Gene Polymorphisms with Prostate Cancer Risk and Androgen Concentrations: Results from the Prostate Cancer Prevention Trial

PubMed Central

Price, Douglas K.; Chau, Cindy H.; Till, Cathee; Goodman, Phyllis J.; Leach, Robin J.; Johnson-Pais, Teresa L.; Hsing, Ann W.; Hoque, Ashraful; Parnes, Howard L.; Schenk, Jeannette M.; Tangen, Catherine M.; Thompson, Ian M.; Reichardt, Juergen K.V.; Figg, William D.

2016-01-01

Background Prostate cancer is highly influenced by androgens and genes. We investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or risk of prostate cancer or high-grade disease from finasteride treatment. Methods A nested case-control study from the Prostate Cancer Prevention Trial using cases drawn from men with biopsy-proven prostate cancer and biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with total, low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. Results There were significant associations of genetic polymorphisms in SRD5A1 (rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with risk of high-grade prostate cancer in the placebo arm of the PCPT; two SNPs were significantly associated with increased risk (SRD5A1 rs472402 [OR, 1.70; 95% CI, 1.05-2.75, Ptrend=0.03]; SRD5A2 rs2300700 [OR, 1.94; 95% CI, 1.19-3.18, Ptrend=0.01]). Eleven SNPs in SRD5A1, SRD5A2, CYP1B1, and CYP3A4 were found to be associated with modifying mean serum androgen and sex hormone-binding globulin concentrations; two SNPs (SRD5A1 rs824811 and CYP1B1 rs10012, Ptrend<0.05) consistently and significantly altered all androgen concentrations. Several SNPs (rs3822430, rs2300700; CYP3A43 rs800672; CYP19 rs700519; Ptrend<0.05) were significantly associated with both circulating hormone levels and prostate cancer risk. Conclusion Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. PMID:27164191

Reduction in physician reimbursement and use of hormone therapy in prostate cancer.

PubMed

Elliott, Sean P; Jarosek, Stephanie L; Wilt, Timothy J; Virnig, Beth A

2010-12-15

hormone therapy for prostate cancer, decreased physician reimbursement was associated with a reduction in overtreatment without a reduction in needed services.

A multidisciplinary prostate cancer clinic for newly diagnosed patients: developing the role of the advanced practice nurse.

PubMed

Madsen, Lydia T; Craig, Catherine; Kuban, Deborah

2009-06-01

Newly diagnosed patients with prostate cancer have various treatment options, and a multidisciplinary prostate cancer clinic (MPCC) can present all options in a single setting. An MPCC was started in 2004 at the University of Texas M.D. Anderson Cancer Center, and 258 patients with prostate cancer were evaluated in its first year. The clinic expanded in 2006 and an oncology advanced practice nurse (APN) was recruited to address specific objectives. The APN role was used to implement a quality-of-life protocol, provide detailed patient education (including a treatment summary and care plan), and serve as a single point of contact as patients move toward a treatment decision. Formal evaluation of the MPCC showed that patients were satisfied with this approach to the complex decision-making process in prostate cancer.

Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat

PubMed Central

Cowin, Prue A.; Foster, Paul; Pedersen, John; Hedwards, Shelley; McPherson, Stephen J.; Risbridger, Gail P.

2008-01-01

Background Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology. Objectives In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring. Methods Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age. Results In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men. Conclusions These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis. PMID:18629315

Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Roychowdhury, Sameek; Goswami, Sangeeta; Ippolito, Joseph E; Priceman, Saul J; Pritchard, Colin C; Sfanos, Karen S; Subudhi, Sumit K; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2017-02-01

The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy.

PubMed

Ma, Qiangzhong; Gomes, Erica M; Lo, Agnes Shuk-Yee; Junghans, Richard P

2014-02-01

Adoptive immunotherapy by infusion of designer T cells (dTc) engineered with chimeric antigen receptors (CARs) for tumoricidal activity represents a potentially highly specific modality for the treatment of cancer. In this study, 2nd generation (gen) anti-prostate specific membrane antigen (PSMA) dTc were developed for improving the efficacy of previously developed 1st gen dTc for prostate cancer immunotherapy. The 1st gen dTc are modified with chimeric immunoglobulin-T cell receptor (IgTCR) while the 2nd gen dTc are engineered with an immunoglobulin-CD28-T cell receptor (IgCD28TCR), which incorporates a CD28 costimulatory signal for optimal T cell activation. A 2nd gen anti-PSMA IgCD28TCR CAR was constructed by inserting the CD28 signal domain into the 1st gen CAR. 1st and 2nd gen anti-PSMA dTc were created by transducing human T cells with anti-PSMA CARs and their antitumor efficacy was compared for specific activation on PSMA-expressing tumor contact, cytotoxicity against PSMA-expressing tumor cells in vitro, and suppression of tumor growth in an animal model. The 2nd gen dTc can be optimally activated to secrete larger amounts of cytokines such as IL2 and IFNγ than 1st gen and to proliferate more vigorously on PSMA-expressing tumor contact. More importantly, the 2nd gen dTc preserve the PSMA-specific cytotoxicity in vitro and suppress tumor growth in animal models with significant higher potency. Our results demonstrate that 2nd gen anti-PSMA designer T cells exhibit superior antitumor functions versus 1st gen, providing a rationale for advancing this improved agent toward clinical application in prostate cancer immunotherapy. © 2013 Wiley Periodicals, Inc.

Epigenetic Regulation in Prostate Cancer Progression.

PubMed

Ruggero, Katia; Farran-Matas, Sonia; Martinez-Tebar, Adrian; Aytes, Alvaro

2018-01-01

An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.

An incidence model of the cost of advanced prostate cancer in Spain.

PubMed

Hart, W M; Nazir, J; Baskin-Bey, E

2014-02-01

Prostate cancer (PCa) is the second leading cancer diagnosed among men. In Spain the incidence of PCa was 70.75 cases per 100,000 males. Advanced PCa has spread outside of the prostate capsule and may involve other parts of the body. The aim of this study was to estimate the lifetime costs of a cohort of advanced PCa patients diagnosed in Spain in 2012. A partitioned economic model was developed in EXCEL incorporating Spanish incidence, mortality, and cost data supplemented with data from the international literature. Progression from Stage III to Stage IV was permitted. Costs were discounted at the standard rate of 3%. Lifetime costs were presented on an individual basis and for the entire cohort of newly diagnosed Stage III and Stage IV PCa patients. Lifetime costs for advanced PCa were ∼€19,961 per patient (mean survival of 8.4 years). Using the projected incident cases for 2012 (3047), the total cost for the incident cohort of patients in 2012 would amount to €61 million. These results were more sensitive to changes in the ongoing costs (post-initial 12 months) of Stage III PCa, the rate of progression from Stage III to Stage IV, and the discount rate applied to costs. This study provides an estimate of the lifetime costs of advanced PCa in Spain and a framework for further research. The study is limited by the availability of long-term Spanish data and the need to make inferences from international studies. However, until long-term prospective or observational data do become available in Spain, based on the assumptions, the current results indicate that the burden of advanced PCa in Spain is substantial. Any treatments that could potentially reduce the economic burden of the disease should be of interest to healthcare decision makers.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial.

PubMed

Kyriakopoulos, Christos E; Chen, Yu-Hui; Carducci, Michael A; Liu, Glenn; Jarrard, David F; Hahn, Noah M; Shevrin, Daniel H; Dreicer, Robert; Hussain, Maha; Eisenberger, Mario; Kohli, Manish; Plimack, Elizabeth R; Vogelzang, Nicholas J; Picus, Joel; Cooney, Matthew M; Garcia, Jorge A; DiPaola, Robert S; Sweeney, Christopher J

2018-04-10

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m 2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Triptorelin for the relief of lower urinary tract symptoms in men with advanced prostate cancer: results of a prospective, observational, grouped-analysis study

PubMed Central

Gil, Thierry; Aoun, Fouad; Cabri, Patrick; Perrot, Valérie; van Velthoven, Roland

2017-01-01

Background: Lower urinary tract symptoms (LUTSs) may develop in men with prostate cancer (PCa) and can impact quality of life (QoL). Gonadotropin-releasing hormone (GnRH) agonists as androgen deprivation therapy are standard treatment for PCa, however, data are limited on their effects on LUTSs. A grouped analysis of national observational, non-interventional studies initiated in clinical practice was performed to assess the effectiveness of triptorelin in reducing moderate or severe LUTSs, measured using the International Prostate Symptom Score (IPSS) in men with advanced or metastatic PCa. Methods: Men with PCa and LUTSs scheduled to receive triptorelin (3-month or 1-month extended release formulation) were recruited into prospective, non-interventional studies at centres in Algeria, Australia, Belgium, China, Hungary, Romania and South Korea. The primary effectiveness endpoint was the proportion of patients with moderate or severe LUTSs, assessed by IPSS, after 48 weeks. Secondary endpoints included: total IPSS, QoL due to urinary symptoms (IPSS Question 8) and prostate-specific antigen (PSA) levels at 24 and 48 weeks. Results: A total of 2701 patients were recruited; 1851 patients with moderate or severe LUTSs at baseline (IPSS > 7), received triptorelin and had follow-up IPSS (efficacy population). The proportion of patients with moderate or severe LUTSs was reduced to 67.2% from baseline at week 48, following a reduction to 75.9% at week 24: the overall time effect was significant (p < 0.001). QoL due to urinary symptoms significantly improved from a mean score of 3.7 at baseline, to adjusted means of 2.5 and 2.1, at weeks 24 and 48, respectively (p < 0.001 versus baseline). Mean PSA levels were reduced from 158.8 ng/ml at baseline to 11.5 and 16.0 ng/ml at weeks 24 and 48, respectively. Conclusions: Within the limitations of these observational studies, improvements in LUTSs and QoL observed after 24 weeks and maintained at 48 weeks indicate that triptorelin

Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial.

PubMed

Price, Douglas K; Chau, Cindy H; Till, Cathee; Goodman, Phyllis J; Leach, Robin J; Johnson-Pais, Teresa L; Hsing, Ann W; Hoque, Ashraful; Parnes, Howard L; Schenk, Jeannette M; Tangen, Catherine M; Thompson, Ian M; Reichardt, Juergen K V; Figg, William D

2016-08-01

Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk. Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional

Androgen-deprivation therapy plus chemotherapy in metastatic hormone-sensitive prostate cancer. A systematic review and meta-analysis of randomized clinical trials.

PubMed

Ramos-Esquivel, Allan; Fernández, Cristina; Zeledón, Zenén

2016-08-01

To assess the efficacy and toxicity of androgen-deprivation therapy (ADT) plus chemotherapy in patients with hormone-sensitive metastatic prostate cancer. Randomized clinical trials were identified after systematic searching of databases and conference proceedings. A random-effect model was used to determine the pooled hazard ratio (HR) for the efficacy outcomes-overall survival (OS), biochemical progression-free survival (PFS), and clinical PFS, according to the inverse-variance method. Heterogeneity was measured using the Q and I(2) statistics. A narrative review was done to explore the major adverse drug reactions reported for each trial. After systematic searching, we included 6 trials (n = 2,675) in this meta-analysis. Estramustine-based chemotherapy plus ADT was not associated with improved OS (HR = 0.64; 95% CI: 0.22-1.89; P = 0.42). In contrast, docetaxel plus ADT was associated with improved OS (HR = 0.75; 95% CI: 0.61-0.91; P = 0.004) and clinical PFS (HR = 0.64; 95% CI: 0.57-0.72; P<0.00001). There was no significant heterogeneity detected among trials. Regarding adverse drug reactions grade 3 or higher, neutropenia was the most frequent side effect reported in a range from 12% to 32%. The addition of docetaxel-based chemotherapy to ADT improves OS and clinical PFS in hormone-sensitive metastatic prostate cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Induction of calcium-dependent nitric oxide synthases by sex hormones.

PubMed

Weiner, C P; Lizasoain, I; Baylis, S A; Knowles, R G; Charles, I G; Moncada, S

1994-05-24

We have examined the effects of pregnancy and sex hormones on calcium-dependent and calcium-independent nitric oxide synthases (NOSs) in the guinea pig. Pregnancy (near term) caused a > 4-fold increase in the activity of calcium-dependent NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal muscle, esophagus, and cerebellum. The increase in NOS activity in the cerebellum during pregnancy was inhibited by the estrogen-receptor antagonist tamoxifen. Treatment with estradiol (but not progesterone) also increased calcium-dependent NOS activity in the tissues examined from both females and males. Testosterone increased calcium-dependent NOS only in the cerebellum. No significant change in calcium-independent NOS activity was observed either during pregnancy or after the administration of any sex hormone. Both pregnancy and estradiol treatment increased the amount of mRNAs for NOS isozymes eNOS and nNOS in skeletal muscle, suggesting that the increases in NOS activity result from enzyme induction. Thus both eNOS and nNOS are subject to regulation by estrogen, an action that could explain some of the changes that occur during pregnancy and some gender differences in physiology and pathophysiology.

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis.

PubMed

Koie, Takuya; Mitsuzuka, Koji; Yoneyama, Takahiro; Narita, Shintaro; Kawamura, Sadafumi; Kaiho, Yasuhiro; Tsuchiya, Norihiko; Tochigi, Tatsuo; Habuchi, Tomonori; Arai, Yoichi; Ohyama, Chikara; Yoneyama, Tohru; Tobisawa, Yuki

2015-10-01

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca. The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS. The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110). Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

Effects of the somatostatin analog lanreotide on the circulating levels of chromogranin-A, prostate-specific antigen, and insulin-like growth factor-1 in advanced prostate cancer patients.

PubMed

Berruti, A; Dogliotti, L; Mosca, A; Tarabuzzi, R; Torta, M; Mari, M; Gorzegno, G; Fontana, D; Angeli, A

2001-05-15

The concept that neuroendocrine cells detected within prostate adenocarcinoma produce paracrine factors, that may exert a proliferative effect on exocrine prostate tumor cells, provides a rationale for the use of somatostatin analogs with the aim to counteract or delay the tumor progression. This study was designed to provide preliminary information on the effect of the administration of a long-acting somatostatin analog, lanreotide, on plasma levels of chromogranin A (CgA). Secondary aims were the evaluation of changes in circulating prostate-specific antigen (PSA) and insulin-like growth factor-1 (IGF-1). Lanreotide (Ipstyl 30 mg; Ipsen, Milan, Italy) was administered intramuscularly every 14 days for 2 months to nine heavily pretreated prostate cancer patients with hormone refractory disease. All patients had, at baseline conditions, CgA values above the normal range. Androgen deprivation was maintained during the study period, while other concomitant antineoplastic treatments were not allowed. Serum PSA levels and plasma CgA and IGF-1 values were measured every week. Lanreotide treatment was very well tolerated and no patient experienced major toxicity. Plasma CgA values at baseline: mean 109 U/liter, standard deviation +/- 85 decreased significantly after treatment as follows: 42 U/liter, +/- 17.8; 27.2 U/liter +/- 13.6; 31.4 U/liter, +/- 17.8 and 27.6 U/liter, +/- 17.0; after 7, 14, 21, and 28 days, respectively (P < 0.01, Friedman ANOVA). Serum PSA did not change. Baseline IGF-1 was found to be above the detection limit in four cases, all of them showing a decrease after lanreotide. Lanreotide administration to prostate cancer patients induces a decrease in plasma CgA and IGF-1 levels, without any influence on serum PSA values. Prostate 47:205-211, 2001. Copyright 2001 Wiley-Liss, Inc.

Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer.

PubMed

Xia, Shu; Kohli, Manish; Du, Meijun; Dittmar, Rachel L; Lee, Adam; Nandy, Debashis; Yuan, Tiezheng; Guo, Yongchen; Wang, Yuan; Tschannen, Michael R; Worthey, Elizabeth; Jacob, Howard; See, William; Kilari, Deepak; Wang, Xuexia; Hovey, Raymond L; Huang, Chiang-Ching; Wang, Liang

2015-06-30

Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer.

Estrogen receptor beta in prostate cancer: friend or foe?

PubMed

Nelson, Adam W; Tilley, Wayne D; Neal, David E; Carroll, Jason S

2014-08-01

Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in prostate carcinogenesis, with evidence resulting from epidemiological, cancer cell line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha (ERA) and estrogen receptor beta (ERB). Most evidence suggests that ERA mediates the harmful effects of estrogen in the prostate, whereas ERB is tumour suppressive, but trials of ERB-selective agents have not translated into improved clinical outcomes. The role of ERB in the prostate remains unclear and there is increasing evidence that isoforms of ERB may be oncogenic. Detailed study of ERB and ERB isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards ERB-dependent pathways. In this review, we summarise evidence on the role of ERB in prostate cancer and highlight areas for future research. © 2014 Society for Endocrinology.

Sirolimus, Docetaxel, and Carboplatin in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

ClinicalTrials.gov

2018-05-25

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Carcinoma Metastatic in the Bone; PSA Level Greater Than or Equal to Two; PSA Progression; Stage IV Prostate Cancer AJCC v7

Trajectories of total depression and depressive symptoms in prostate cancer patients receiving six months of hormone therapy.

PubMed

Sharpley, Christopher F; Christie, David R H; Bitsika, Vicki; Miller, Bradley J

2017-01-01

The aim of this study was to investigate the effects of hormone therapy (HT) on depression and depressive symptoms in prostate cancer patients undergoing 6 months of HT. One hundred two prostate cancer patients who had been prescribed HT completed the Zung Self-rating Depression Scale (SDS) and two questions about their sexual enjoyment and performance, plus a background questionnaire before HT, after 8 to 10 weeks of HT and again after 16 to 20 weeks of HT. There was a significant increase in SDS scores from before to during HT. High depression score before HT was a significant predictor of later increases in depression during HT. Increases in depressive symptoms were restricted to 8 of the 20 SDS symptoms, the most powerful change being in sexual anhedonia, which was a result of decreased ability to perform during sexual activity. The association between HT and elevated depression is confirmed, but the relative influence of sexual anhedonia over other depressive symptoms expands the understanding of this association. The effects of decreased ability to perform during sex appear to dominate the increase in depression during HT. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A zinc-dependent epitope on the molecule of thymulin, a thymic hormone.

PubMed Central

Dardenne, M; Savino, W; Berrih, S; Bach, J F

1985-01-01

Thymulin is a nonapeptide hormone produced by thymic epithelial cells. Its biological activity is strictly dependent on the presence of the metal zinc in the molecule. Antithymulin monoclonal antibodies have been produced against either the synthetic (AS1) or the natural intraepithelial (AE1) molecule. These monoclonal antibodies were screened for their abilities to inhibit the zinc-dependent biological activity of the hormone and were shown to bind to thymic epithelial cells. By using biological and immunofluorescence assays, the two antibodies were shown to recognize exclusively the zinc-coupled thymulin molecule. Other antithymulin antibodies screened by RIA or ELISA (using a zinc-deprived substrate) recognized a zinc-independent epitope on the thymulin molecule. These data indicate the existence of a zinc-specific conformation on the thymulin molecule. They are in agreement with NMR studies showing that the zinc-containing hormone has a unique structure. Images PMID:2413455

Can Mathematical Models Predict the Outcomes of Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy?

NASA Astrophysics Data System (ADS)

Everett, R. A.; Packer, A. M.; Kuang, Y.

Androgen deprivation therapy is a common treatment for advanced or metastatic prostate cancer. Like the normal prostate, most tumors depend on androgens for proliferation and survival but often develop treatment resistance. Hormonal treatment causes many undesirable side effects which significantly decrease the quality of life for patients. Intermittently applying androgen deprivation in cycles reduces the total duration with these negative effects and may reduce selective pressure for resistance. We extend an existing model which used measurements of patient testosterone levels to accurately fit measured serum prostate specific antigen (PSA) levels. We test the model's predictive accuracy, using only a subset of the data to find parameter values. The results are compared with those of an existing piecewise linear model which does not use testosterone as an input. Since actual treatment protocol is to re-apply therapy when PSA levels recover beyond some threshold value, we develop a second method for predicting the PSA levels. Based on a small set of data from seven patients, our results showed that the piecewise linear model produced slightly more accurate results while the two predictive methods are comparable. This suggests that a simpler model may be more beneficial for a predictive use compared to a more biologically insightful model, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting. Nevertheless, both models are an important step in this direction.

Can Mathematical Models Predict the Outcomes of Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy?

NASA Astrophysics Data System (ADS)

Everett, R. A.; Packer, A. M.; Kuang, Y.

2014-04-01

Androgen deprivation therapy is a common treatment for advanced or metastatic prostate cancer. Like the normal prostate, most tumors depend on androgens for proliferation and survival but often develop treatment resistance. Hormonal treatment causes many undesirable side effects which significantly decrease the quality of life for patients. Intermittently applying androgen deprivation in cycles reduces the total duration with these negative effects and may reduce selective pressure for resistance. We extend an existing model which used measurements of patient testosterone levels to accurately fit measured serum prostate specific antigen (PSA) levels. We test the model's predictive accuracy, using only a subset of the data to find parameter values. The results are compared with those of an existing piecewise linear model which does not use testosterone as an input. Since actual treatment protocol is to re-apply therapy when PSA levels recover beyond some threshold value, we develop a second method for predicting the PSA levels. Based on a small set of data from seven patients, our results showed that the piecewise linear model produced slightly more accurate results while the two predictive methods are comparable. This suggests that a simpler model may be more beneficial for a predictive use compared to a more biologically insightful model, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting. Nevertheless, both models are an important step in this direction.

Comparison of composite prostate radiotherapy plan doses with dependent and independent boost phases.

PubMed

Narayanasamy, Ganesh; Avila, Gabrielle; Mavroidis, Panayiotis; Papanikolaou, Niko; Gutierrez, Alonso; Baacke, Diana; Shi, Zheng; Stathakis, Sotirios

2016-09-01

Prostate cases commonly consist of dual phase planning with a primary plan followed by a boost. Traditionally, the boost phase is planned independently from the primary plan with the risk of generating hot or cold spots in the composite plan. Alternatively, boost phase can be planned taking into account the primary dose. The aim of this study was to compare the composite plans from independently and dependently planned boosts using dosimetric and radiobiological metrics. Ten consecutive prostate patients previously treated at our institution were used to conduct this study on the Raystation™ 4.0 treatment planning system. For each patient, two composite plans were developed: a primary plan with an independently planned boost and a primary plan with a dependently planned boost phase. The primary plan was prescribed to 54 Gy in 30 fractions to the primary planning target volume (PTV1) which includes prostate and seminal vesicles, while the boost phases were prescribed to 24 Gy in 12 fractions to the boost planning target volume (PTV2) that targets only the prostate. PTV coverage, max dose, median dose, target conformity, dose homogeneity, dose to OARs, and probabilities of benefit, injury, and complication-free tumor control (P+) were compared. Statistical significance was tested using either a 2-tailed Student's t-test or Wilcoxon signed-rank test. Dosimetrically, the composite plan with dependent boost phase exhibited smaller hotspots, lower maximum dose to the target without any significant change to normal tissue dose. Radiobiologically, for all but one patient, the percent difference in the P+ values between the two methods was not significant. A large percent difference in P+ value could be attributed to an inferior primary plan. The benefits of considering the dose in primary plan while planning the boost is not significant unless a poor primary plan was achieved.

Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial

PubMed Central

Tang, Li; Yao, Song; Till, Cathee; Goodman, Phyllis J.; Tangen, Catherine M.; Wu, Yue; Kristal, Alan R.; Platz, Elizabeth A.; Neuhouser, Marian L.; Stanczyk, Frank Z.; Reichardt, Juergen K.V.; Santella, Regina M.; Hsing, Ann; Hoque, Ashraful; Lippman, Scott M.; Thompson, Ian M.; Ambrosone, Christine B.

2011-01-01

The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16–2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)n repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (≥7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05–1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment. PMID:21771722

takeout-dependent longevity is associated with altered Juvenile Hormone signaling

PubMed Central

Chamseddin, Khalil H.; Khan, Sabina Q.; Nguyen, Mai L.H.; Antosh, Michael; Morris, Siti Nur Sarah; Kolli, Santharam; Neretti, Nicola; Helfand, Stephen L.; Bauer, Johannes H.

2012-01-01

In order to understand the molecular mechanisms of longevity regulation, we recently performed a screen designed to enrich for genes common to several longevity interventions. Using this approach, we identified the Drosophila melanogaster gene takeout. takeout is upregulated in a variety of long-lived flies, and extends life span when overexpressed. Here, we investigate the mechanisms of takeout-dependent longevity. takeout overexpression specifically in the fat body is sufficient to increase fly longevity and is additive to the longevity effects of dietary restriction. takeout long-lived flies do not show phenotypes often associated with increased longevity, such as enhanced stress resistance or major metabolic abnormalities. However, males exhibit greatly diminished courtship behavior, leading to a reduction in fertility. Interestingly, takeout contains a binding domain for Juvenile Hormone, a fly hormone that plays a role in the regulation of developmental transitions. Importantly, the longevity and courtship phenotypes of takeout overexpressing flies are reversed by treatment with the Juvenile Hormone analog methoprene. These data suggest that takeout is a key player in the tradeoff-switch between fertility and longevity. takeout may control fertility via modulation of courtship behavior. This regulation may occur through Juvenile Hormone binding to takeout and a subsequent reduction in Juvenile Hormone signaling activity. PMID:22940452

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences

PubMed Central

Quagliariello, Vincenzo; Rossetti, Sabrina; Cavaliere, Carla; Di Palo, Rossella; Lamantia, Elvira; Castaldo, Luigi; Nocerino, Flavia; Ametrano, Gianluca; Cappuccio, Francesca; Malzone, Gabriella; Montanari, Micaela; Vanacore, Daniela; Romano, Francesco Jacopo; Piscitelli, Raffaele; Iovane, Gelsomina; Pepe, Maria Filomena; Berretta, Massimiliano; D'Aniello, Carmine; Perdonà, Sisto; Muto, Paolo; Botti, Gerardo; Ciliberto, Gennaro; Veneziani, Bianca Maria; De Falco, Francesco; Maiolino, Piera; Caraglia, Michele; Montella, Maurizio; Iaffaioli, Rosario Vincenzo; Facchini, Gaetano

2017-01-01

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the worlds leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease. PMID:28389628

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.

PubMed

Quagliariello, Vincenzo; Rossetti, Sabrina; Cavaliere, Carla; Di Palo, Rossella; Lamantia, Elvira; Castaldo, Luigi; Nocerino, Flavia; Ametrano, Gianluca; Cappuccio, Francesca; Malzone, Gabriella; Montanari, Micaela; Vanacore, Daniela; Romano, Francesco Jacopo; Piscitelli, Raffaele; Iovane, Gelsomina; Pepe, Maria Filomena; Berretta, Massimiliano; D'Aniello, Carmine; Perdonà, Sisto; Muto, Paolo; Botti, Gerardo; Ciliberto, Gennaro; Veneziani, Bianca Maria; De Falco, Francesco; Maiolino, Piera; Caraglia, Michele; Montella, Maurizio; Iaffaioli, Rosario Vincenzo; Facchini, Gaetano

2017-05-02

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

How does initial treatment choice affect short-term and long-term costs for clinically localized prostate cancer?

PubMed

Snyder, Claire F; Frick, Kevin D; Blackford, Amanda L; Herbert, Robert J; Neville, Bridget A; Carducci, Michael A; Earle, Craig C

2010-12-01

Data regarding costs of prostate cancer treatment are scarce. This study investigates how initial treatment choice affects short-term and long-term costs. This retrospective, longitudinal cohort study followed prostate-cancer cases diagnosed in 2000 for 5 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Men age≥66 years, in Medicare fee for service, diagnosed with clinically localized prostate cancer in 2000 while residing in a SEER region, were matched to noncancer controls using age, sex, race, region, comorbidity, and survival. On the basis of treatment received during the first 9 months postdiagnosis, patients were assigned to watchful waiting, radiation, hormonal therapy, hormonal+radiation, and surgery (may have received other treatments). Incremental costs for prostate cancer were the difference in costs for prostate cancer cases versus matched controls. Costs were divided into initial treatment (months -1 to 12), long-term (each 12 months thereafter), and total (months -1 to 60). Sensitivity analyses excluded the last 12 months of life. A total of 13,769 prostate-cancer cases were matched to 13,769 noncancer controls. Watchful waiting had the lowest initial treatment ($4270) and 5-year total costs ($9130). Initial treatment costs were highest for hormonal+radiation ($17,474) and surgery ($15,197). At $26,896, 5-year total costs were highest for hormonal therapy only followed by hormonal+radiation ($25,097) and surgery ($19,214). After excluding the last 12 months of life, total costs were highest for hormonal+radiation ($23,488) and hormonal therapy ($23,199). Patterns of costs vary widely based on initial treatment. These data can inform patients and clinicians considering treatment options and policy makers interested in patterns of costs. Copyright © 2010 American Cancer Society.

[Role of angiotensin II receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer].

PubMed

Chibichyan, M B; Kogan, M I; Chernogubova, E A; Pavlenko, I A; Matishov, D G

2016-12-01

To identify markers for predicting aggressive forms of prostate cancer. The study retrospectively evaluated expression of angiotensin II type 2 receptors (AT2-R) in prostate needle biopsy tissue from patients with and without biochemical recurrence after combined hormone and radiation therapy. The study findings showed that low expression of AT2-R in prostate tissue was associated with a high risk of biochemical recurrence. The data on the nature of AT2-R expression in prostate tissue of prostate cancer patients may be considered as a tool for predicting biochemical recurrence after combined hormone and radiation therapy. The test has a sensitivity of 87.5% and specificity of 85.71%.

Treatment of gynecomastia in patients with prostate cancer and androgen deprivation.

PubMed

Bautista-Vidal, C; Barnoiu, O; García-Galisteo, E; Gómez-Lechuga, P; Baena-González, V

2014-01-01

Gynecomastia, defined as benign proliferation of glandular breast tissue has a prevalence of 32% to 72% in the male. In the urology setting, it is associated to patients with prostate cancer and hormone treatment with a prevalence of 15% in the case of complete hormone blockage and 75% in monotherapy. The different options of treatment in prostate cancer have changed in recent decades. Thus, we have focused on this subject to evaluate the different therapy options of hormone manipulation induced gynecomastia in prostate cancer patients. To synthesize the available evidence on the different therapeutic options in prostate cancer patients who develop gynecomastia due to the use of nonsteroidal antiandrogens and to generate a diagnostic algorithm and treatment. Using the PICO type structured search strategy (Patient or problem, Intervention, Comparison, Outcome or result) in the data bases of PubMed-Medline and Cochrane, identification was made of the relevant studies related to the treatment of gynecomastia in Prostate Cancer patients treated with nonsteroidal antiandrogens. We have found 3 possible therapeutic options for the treatment of gynecomastia and mastodynia in patients with hormone deprivation therapy for prostate cancer. The 10Gy radiotherapy would be an option for the treatment of gynecomastia, although not all the patients need prophylactic treatment since only 50% report moderate-severe discomfort. Another option is the use of drugs such as tamoxifen 20mg/day that lead to a significant decrease in the mammary effects. Gynecomastia and mastodynia, given their high incidence, make the physical examination a fundamental tool for all patients before initiating treatment with antiandrogens. The use of tamoxifen 20mg/day is the best treatment and prevention option against gynecomastia and mastodynia, while in the case of long-course established gynecomastia, surgery is the gold standard. Copyright © 2012 AEU. Published by Elsevier Espana. All rights reserved.

Substance use disorder and its effects on outcomes in men with advanced-stage prostate cancer.

PubMed

Chhatre, Sumedha; Metzger, David S; Malkowicz, S Bruce; Woody, George; Jayadevappa, Ravishankar

2014-11-01

Substance use disorder in patients with cancer has implications for outcomes. The objective of this study was to analyze the effects of the type and timing of substance use on outcomes in elderly Medicare recipients with advanced prostate cancer. This was an observational cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data from 2000 to 2009. Among men who were diagnosed with advanced prostate cancer between 2001 and 2004, we identified those who had a claim for substance use disorder in the year before cancer diagnosis, 1 year after cancer diagnosis, and an additional 4 years after diagnosis. The outcomes investigated were use of health services, costs, and mortality. The prevalence of substance use disorder was 10.6%. The category drug psychoses and related had greater odds of inpatient hospitalizations (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-2.8), outpatient hospital visits (OR, 2.6; 95% CI, 1.9-3.6), and emergency room visits (OR, 1.7; 95% CI, 1.2-2.4). Substance use disorder in the follow-up phase was associated with greater odds of inpatient hospitalizations (OR, 2.0; 95% CI, 1.8-2.2), outpatient hospital visits (OR, 2.0; 95% CI, 1.7-2.4), and emergency room visits (OR, 1.7; 95% CI, 1.5-2.1). Compared with men who did not have substance use disorder, those in the category drug psychoses and related had 70% higher costs, and those who had substance use disorder during the follow-up phase had 60% higher costs. The hazard of all-cause mortality was highest for patients in the drug psychoses and related category (hazard ratio, 1.3; 95% CI, 1.1-1.7) and the substance use disorder in treatment phase category (hazard ratio, 1.5; 95% CI, 1.3-1.7). The intersection of advanced prostate cancer and substance use disorder may adversely affect outcomes. Incorporating substance use screening and treatments into prostate cancer care guidelines and coordination of care is desirable. © 2014 American Cancer Society.

Radium-223 IN metastatic hormone-sensitive high-grade prostate cancer: initial experience.

PubMed

Osvaldo, García-Pérez Francisco; Salvador, Medina-Ornelas Sevastián; Zael, Santana-Ríos; Nora, Sobrevilla-Moreno

2017-01-01

Our study evaluates the feasibility of compassionate exemption of Radium-223 ( 223 Ra) treatment in metastatic hormone-sensitive high-grade prostate cancer (mHSHGPC) patients with concomitant androgen deprivation-therapy (ADT). Seven patients with mHSHGPC, were treated with six cycles of 223 Ra plus ADT. All patients had undergone to 18 F-NaF-PET/CT. A qualitative analyses of the 18 F-NaF-PET/CT was performed in conjunction with Alkaline Phosphatase (ALP), Lactate-dehydrogenase (LDH) and Prostatic-Specific Antigen (PSA) values. The mean of SUVmax values were used as a quantitative measure of tumoral burden. Changes in PSA, ALP, LDH from baseline were evaluated, and were defined as increase or decrease of at least 30%. Clinical response was achieved if there was pain reduction using visual analogic scale. Four patients showed a significant reduction in mean SUVmax after 3 cycles of 223 Ra, and one after 6 cycles. Patients who showed reductions in mean SUVmax after Ra-223 also showed reductions in PSA, ALP and LDH. Four weeks after the last cycle of 223 Ra all patients had decreased total PSA, ALP and LDH values ≥ 30% also significant improvement on pain. No progress disease was documented after 14 ± 4 weeks. We found slight to moderate decreases in neutrophils and hemoglobin in two patients. We concluded that 223 Ra plus ADT can be useful in mHSHGPC; the semi-quantitative 18 F-NaF-PET/CT as a method effective to monitor the treatment response. Due to concomitant administration of ADT, 18 F-NaF-PET/CT cannot differentiate whether the findings were due to androgen blockade or the 223 Ra; nevertheless, data supporting the efficacy of 223 Ra is the significant improvement on pain.

Adjuvant Chemotherapy Improves Prostate Cancer Survival

Cancer.gov

Giving some men with prostate cancer chemotherapy after standard treatment with radiation and hormone therapy modestly improves how long they live, according to results from a new NCI-funded clinical trial.

Nucleoporin 62 and Ca(2+)/calmodulin dependent kinase kinase 2 regulate androgen receptor activity in castrate resistant prostate cancer cells.

PubMed

Karacosta, Loukia G; Kuroski, Laura A; Hofmann, Wilma A; Azabdaftari, Gissou; Mastri, Michalis; Gocher, Angela M; Dai, Shuhang; Hoste, Allen J; Edelman, Arthur M

2016-02-15

Re-activation of the transcriptional activity of the androgen receptor (AR) is an important factor mediating progression from androgen-responsive to castrate-resistant prostate cancer (CRPC). However, the mechanisms regulating AR activity in CRPC remain incompletely understood. Ca(2+) /calmodulin-dependent kinase kinase (CaMKK) 2 was previously shown to regulate AR activity in androgen-responsive prostate cancer cells. Our objective was to further explore the basis of this regulation in CRPC cells. The abundance of CaMKK2 in nuclear fractions of androgen-responsive prostate cancer and CRPC, cells were determined by subcellular fractionation and Western blotting. CaMKK2 association with nuclear pore complexes (NPCs) and nucleoporins (Nups) including Nup62, were imaged by structured illumination and super-resolution fluorescence microscopy and co-immunoprecipitation, respectively. The abundance and subcellular localization of CaMKK2 and Nup62 in human clinical specimens of prostate cancer was visualized by immunohistochemistry. The role of Nups in the growth and viability of CRPC cells was assessed by RNA interference and cell counting. The involvement of CaMKK2 and Nup62 in regulating AR transcriptional activity was addressed by RNA interference, chromatin immunoprecipitation, androgen response element reporter assay, and Western blotting. CaMKK2 was expressed at higher levels in the nuclear fraction of CPRC C4-2 cells, than in that of androgen-responsive LNCaP cells. In C4-2 cells, CaMKK2 associated with NPCs of the nuclear envelope and physically interacted with Nup62. CaMKK2 and Nup62 demonstrated pronounced, and similar increases in both expression and perinuclear/nuclear localization in human clinical specimens of advanced prostate cancer relative to normal prostate. Knockdown of Nup62, but not of Nups, 98 or 88, reduced growth and viability of C4-2 cells. Knockdown of Nup62 produced a greater reduction of the growth and viability of C4-2 cells than of non

Prostate cancer: The main risk and protective factors-Epigenetic modifications.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Dagdemir, Aslihan; Judes, Gaëlle; Pajon, Amaury; Karsli-Ceppioglu, Seher; Penault-Llorca, Frédérique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2015-02-01

With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial - there are non-modifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet-cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer

PubMed Central

Siddiqui, Imtiaz A.; Asim, Mohammad; Hafeez, Bilal B.; Adhami, Vaqar M.; Tarapore, Rohinton S.; Mukhtar, Hasan

2011-01-01

Androgen deprivation therapy is the major treatment for advanced prostate cancer (PCa). However, it is a temporary remission, and the patients almost inevitably develop hormone refractory prostate cancer (HRPC). HRPC is almost incurable, although most HRPC cells still express androgen receptor (AR) and depend on the AR for growth, making AR a prime drug target. Here, we provide evidence that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is a direct antagonist of androgen action. In silico modeling and FRET-based competition assay showed that EGCG physically interacts with the ligand-binding domain of AR by replacing a high-affinity labeled ligand (IC50 0.4 μM). The functional consequence of this interaction was a decrease in AR-mediated transcriptional activation, which was due to EGCG mediated inhibition of interdomain N-C termini interaction of AR. Treatment with EGCG also repressed the transcriptional activation by a hotspot mutant AR (T877A) expressed ectopically as well as the endogenous AR mutant. As the physiological consequence of AR antagonism, EGCG repressed R1881-induced PCa cell growth. In a xenograft model, EGCG was found to inhibit AR nuclear translocation and protein expression. We also observed a significant down-regulation of androgen-regulated miRNA-21 and up-regulation of a tumor suppressor, miRNA-330, in tumors of mice treated with EGCG. Taken together, we provide evidence that EGCG functionally antagonizes androgen action at multiple levels, resulting in inhibition of PCa growth.—Siddiqui, I. A., Asim, M., Hafeez, B. B., Adhami, V. M., Tarapore, R. S., Mukhtar, H. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. PMID:21177307

[Characteristics of polyamine biosynthesis regulation and tumor growth rate in hormone-dependant grafted breast tumors of mice and rats].

PubMed

Orlovskiĭ, A A

2007-01-01

Effect of the inhibitors of polyamines biosynthesis on completely or partially hormone-dependant breast tumors (mouse Ca755 carcinoma and Walker W-256 carcinosarcoma) is essentially special: in contrary to hormone-dependant tumors, this effect may be not only breaking but stimulating as well. Change-over from one to another mode of reaction is conditioned, most probable, by hormonal status, which is determined by one or another estral cycle phase. Biochemical mechanisms of this change-over are closely connected with polyamines metabolism, namely the degree of polyamines (especially spermine) interconvertion and physiological reactivity level of the system controlling expression of ornithin-decarboxilase. At that, the first of these pathways is predominant for completely hormone-dependant Ca755 and the second one -for partially hormone-dependant W-256.

Increasing use of radical prostatectomy for locally advanced prostate cancer in the USA and Germany: a comparative population-based study.

PubMed

Hager, B; Kraywinkel, K; Keck, B; Katalinic, A; Meyer, M; Zeissig, S R; Scheufele, R; Wirth, M P; Huber, J

2017-03-01

Current guidelines do not recommend a preferred treatment modality for locally advanced prostate cancer. The aim of the study was to compare treatment patterns found in the USA and Germany and to analyze possible trends over time. We compared 'Surveillance Epidemiology and End Results' (SEER) data (USA) with reports from four German federal epidemiological cancer registries (Eastern Germany, Bavaria, Rhineland-Palatinate, Schleswig-Holstein), both from 2004 to 2012. We defined locally advanced prostate cancer as clinical stage T3 or T4. Exclusion criteria were metastatic disease and age over 79 years. We identified 9127 (USA) and 11 051 (Germany) patients with locally advanced prostate cancer. The share was 2.1% in the USA compared with 6.0% in Germany (P<0.001). In the United States, the utilization of radiotherapy (RT) and radical prostatectomy (RP) was comparably high with 42.0% (RT) and 42.8% (RP). In Germany, the major treatment option was RP with 36.7% followed by RT with 22.1%. During the study period, the use of RP increased in both countries (USA P=0.001 and Germany P=0.003), whereas RT numbers declined (USA P=0.003 and Germany P=0.002). The share of adjuvant RT (aRT) was similar in both countries (USA 21.7% vs Germany 20.7%). We found distinctive differences in treating locally advanced prostate cancer between USA and Germany, but similar trends over time. In the last decade, a growing number of patients underwent RP as a possible first step within a multimodal concept.

Cyclin K dependent regulation of Aurora B affects apoptosis and proliferation by induction of mitotic catastrophe in prostate cancer.

PubMed

Schecher, Sabrina; Walter, Britta; Falkenstein, Michael; Macher-Goeppinger, Stephan; Stenzel, Philipp; Krümpelmann, Kristina; Hadaschik, Boris; Perner, Sven; Kristiansen, Glen; Duensing, Stefan; Roth, Wilfried; Tagscherer, Katrin E

2017-10-15

Cyclin K plays a critical role in transcriptional regulation as well as cell development. However, the role of Cyclin K in prostate cancer is unknown. Here, we describe the impact of Cyclin K on prostate cancer cells and examine the clinical relevance of Cyclin K as a biomarker for patients with prostate cancer. We show that Cyclin K depletion in prostate cancer cells induces apoptosis and inhibits proliferation accompanied by an accumulation of cells in the G2/M phase. Moreover, knockdown of Cyclin K causes mitotic catastrophe displayed by multinucleation and spindle multipolarity. Furthermore, we demonstrate a Cyclin K dependent regulation of the mitotic kinase Aurora B and provide evidence for an Aurora B dependent induction of mitotic catastrophe. In addition, we show that Cyclin K expression is associated with poor biochemical recurrence-free survival in patients with prostate cancer treated with an adjuvant therapy. In conclusion, targeting Cyclin K represents a novel, promising anti-cancer strategy to induce cell cycle arrest and apoptotic cell death through induction of mitotic catastrophe in prostate cancer cells. Moreover, our results indicate that Cyclin K is a putative predictive biomarker for clinical outcome and therapy response for patients with prostate cancer. © 2017 UICC.

Sex Steroid Metabolism in Benign and Malignant Intact Prostate Biopsies: Individual Profiling of Prostate Intracrinology

PubMed Central

Gianfrilli, Daniele; Pierotti, Silvia; Leonardo, Costantino; Ciccariello, Mauro

2014-01-01

In vitro studies reveal that androgens, oestrogens, and their metabolites play a crucial role in prostate homeostasis. Most of the studies evaluated intraprostatic hormone metabolism using cell lines or preprocessed specimens. Using an ex vivo model of intact tissue cultures with preserved architecture, we characterized the enzymatic profile of biopsies from patients with benign prostatic hyperplasia (BPH) or cancer (PC), focusing on 17β-hydroxy-steroid-dehydrogenases (17β-HSDs) and aromatase activities. Samples from 26 men who underwent prostate needle core biopsies (BPH n = 14; PC n = 12) were incubated with radiolabeled 3H-testosterone or 3H-androstenedione. Conversion was evaluated by TLC separation and beta-scanning of extracted supernatants. We identified three major patterns of conversion. The majority of BPHs revealed no active testosterone/oestradiol conversion as opposed to prostate cancer. Conversion correlated with histology and PSA, but not circulating hormones. Highest Gleason scores had a higher androstenedion-to-testosterone conversion and expression of 17β-HSD-isoenzymes-3/5. Conclusions. We developed an easy tool to profile individual intraprostatic enzymatic activity by characterizing conversion pathways in an intact tissue environment. In fresh biopsies we found that 17β-HSD-isoenzymes and aromatase activities correlate with biological behaviour allowing for morphofunctional phenotyping of pathology specimens and clinical monitoring of novel enzyme-targeting drugs. PMID:25184140

Multivalent Peptidomimetic Conjugates as Inhibitors of Androgen Receptor Function in Therapy Resistant Prostate Cancer

DTIC Science & Technology

2016-10-01

hormones that play a critical role in stimulating prostate cancer growth . Androgens activate a protein called the androgen receptor (AR), which...5-15 3 1. INTRODUCTION: Androgens are hormones that play a critical role in stimulating prostate cancer growth . Androgens...regulates genes involved in cell growth . Although powerful anti-androgen drugs can be administered to block AR action and have been used successfully to

Definition of molecular determinants of prostate cancer cell bone extravasation.

PubMed

Barthel, Steven R; Hays, Danielle L; Yazawa, Erika M; Opperman, Matthew; Walley, Kempland C; Nimrichter, Leonardo; Burdick, Monica M; Gillard, Bryan M; Moser, Michael T; Pantel, Klaus; Foster, Barbara A; Pienta, Kenneth J; Dimitroff, Charles J

2013-01-15

Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.

A prospective investigation of height and prostate cancer risk.

PubMed

Sequoia, Jacqueline S P; Wright, Margaret E; McCarron, Peter; Pietinen, Pirjo; Taylor, Philip R; Virtamo, Jarmo; Albanes, Demetrius

2006-11-01

Greater adult height, which reflects a combination of early nutrition, exposure to androgens, growth hormones, and other factors during growth and development, as well as heredity, has been associated with increased prostate cancer risk in several observational studies, but findings have been inconsistent. We examined this relationship in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. At baseline, 29,119 Finnish male smokers 50 to 69 years old had height and weight measured by trained personnel, provided information on demographic, smoking, medical, and other characteristics, and completed an extensive diet history questionnaire. A total of 1,346 incident prostate cancer cases were identified during a follow-up period of up to 17.4 years (median, 14.1 years). In age-adjusted Cox proportional hazards models, the hazard ratios and 95% confidence intervals for prostate cancer according to increasing quintiles of height [178 cm] were 1.00 (reference), 1.11 (0.93-1.32), 1.11 (0.95-1.31), 1.30 (1.01-1.55), and 1.14 (0.96-1.35); P(trend) = 0.04. In analyses stratified by disease stage (available for 916 cases), a strong dose-response relationship was observed between greater height and advanced, but not earlier-stage, disease [tumor-node-metastasis stage III-IV, hazard ratio and 95% confidence interval for increasing quintiles of height: 1.77 (1.18-2.65), 1.82 (1.25-2.65), 1.93 (1.29-2.90), and 2.02 (1.37-2.97); P(trend) = 0.0008, P(interaction) = 0.002]. Our study provides additional evidence that increased height is a risk factor for prostate cancer and suggests that taller men are particularly susceptible to advanced disease.

Reduction in Physician Reimbursement and Use of Hormone Therapy in Prostate Cancer

PubMed Central

Jarosek, Stephanie L.; Wilt, Timothy J.; Virnig, Beth A.

2010-01-01

2004–2005. Conclusions In this example of hormone therapy for prostate cancer, decreased physician reimbursement was associated with a reduction in overtreatment without a reduction in needed services. PMID:21131577

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

PubMed Central

Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

2017-01-01

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

Impact of Oxidative Stress Biomarkers and Carboxymethyllysine (An Advanced Glycation End Product) on Prostate Cancer: A Prospective Study

PubMed Central

Yang, Shuman; Pinney, Susan M.; Mallick, Palash; Ho, Shuk-Mei; Bracken, Bruce; Wu, Tianying

2015-01-01

Introduction Biomarkers of oxidative stress and advanced glycation end products (AGE) have been linked to the development of prostate cancer, but evidence from human studies is either scarce or controversial. Materials and Methods We conducted a prospective nested case-control study among 48 men (24 prostate cancer cases and 24 controls) aged 48–76 years at baseline. The participants of our study were a part of the Fernald Community Cohort (FCC). Prostate cancer cases and controls were matched individually on age (± 3 years) with 1:1 ratio. Biomarkers included urine F2-isoprostanes (markers of lipid oxidation), plasma fluorescent oxidation products (FlOPs; markers of global oxidation) and carboxymethyllysine (CML; a major end-stage AGE). Results At baseline, cases had similar age, body mass index, proportion of family history of prostate cancer, history of benign prostatic hyperplasia, history of hypertension, history of diabetes, smokers and plasma glucose levels as compared to controls. Levels of plasma CML were significantly higher in cases than in controls (182 vs. 152 μg/ml, P < 0.05). In the conditional logistic regression model, an increase in CML equivalent to one standard deviation was associated with increased risk of incident prostate cancer (Relative risk = 1.79, 95% confidence interval = 1.00–3.21), and accounted for ~8% variance of prostate cancer liability. Urine F2-isoprostanes and plasma FlOPs were not associated with prostate cancer incidence. Conclusion Higher levels of plasma CML were associated with increased risk of prostate cancer. This suggests a potential new pathway for prostate cancer prediction and treatment. PMID:25972296

Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.

PubMed

Angulo, Javier C; Andrés, Guillermo; Ashour, Nadia; Sánchez-Chapado, Manuel; López, Jose I; Ropero, Santiago

2016-03-01

Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer. Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis. We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases. Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It

Antibody Responses to Prostate-Associated Antigens in Patients with Prostatitis and Prostate Cancer

PubMed Central

Maricque, Brett B.; Eickhoff, Jens C.; McNeel, Douglas G.

2010-01-01

Background An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens, however prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer. Methods Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n=126), patients with chronic prostatitis (n=45), and men without prostate disease (n=53). Results We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (p<0.001 and p=0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression. Conclusions These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue. PMID:20632317

Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

DTIC Science & Technology

2011-05-01

8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

Triptorelin 6-month formulation in the management of patients with locally advanced and metastatic prostate cancer: an open-label, non-comparative, multicentre, phase III study.

PubMed

Lundström, Eija A; Rencken, Rupert K; van Wyk, Johann H; Coetzee, Lance J E; Bahlmann, Johann C M; Reif, Simon; Strasheim, Erdam A; Bigalke, Martin C; Pontin, Alan R; Goedhals, Louis; Steyn, Douw G; Heyns, Chris F; Aldera, Luigi A; Mackenzie, Thomas M; Purcea, Daniela; Grosgurin, Pierre Y; Porchet, Hervé C

2009-01-01

Triptorelin 6-month formulation was developed to offer greater convenience to both patients and physicians by reducing the injection frequency. The efficacy, pharmacokinetics and safety of a new 6-month formulation of triptorelin were investigated over 12 months (48 weeks). The primary objective was to evaluate the formulation in achieving castrate serum testosterone levels (< or = 1.735 nmol/L or < or = 50 ng/dL) on day 29 and in maintaining castration at months 2-12. Absence of luteinizing hormone (LH) stimulation and change in prostate-specific antigen (PSA) level were also assessed. An open-label, non-comparative, phase III study in 120 patients with advanced prostate cancer was conducted from July 2006 to August 2007 in private and public institutions in South Africa. Each patient received two consecutive intramuscular injections of triptorelin embonate (pamoate) 22.5 mg at an interval of 24 weeks. In all patients, testosterone (primary outcome measurement) was measured at baseline and then every 4 weeks; LH was measured before and 2 hours after the two injections. PSA was measured on day 1 and at weeks 12, 24, 36 and 48. Adverse events were recorded at each visit. In the intent-to-treat population, 97.5% (95% CI 92.9, 99.5) of patients achieved castrate serum testosterone levels by day 29, and 93.0% (95% CI 86.8, 97.0) maintained castration at months 2-12. After the second injection, 98.3% of patients showed absence of LH stimulation. The most frequent drug-related adverse events were hot flushes (71.7% of patients). No patient withdrew from the study as a result of an adverse event. The triptorelin 6-month formulation was well tolerated and was able to achieve and maintain castration for the treatment of locally advanced and metastatic prostate cancer. By reducing the frequency of required injections, this new formulation offers a more convenient treatment regimen. (Clinical Trial Registration,NCT00751790 at www.clinicaltrials.gov).

FDA Approves Apalutamide for Prostate Cancer

Cancer.gov

Apalutamide (Erleada) is a hormone therapy that counteracts resistance to androgen deprivation therapy. Learn more about the FDA approval of apalutamide for men with castration-resistant nonmetastatic prostate cancer in this Cancer Currents blog post.

Digoxin and prostate cancer survival in the Finnish Randomized Study of Screening for Prostate Cancer.

PubMed

Kaapu, Kalle J; Murtola, Teemu J; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo Lj; Auvinen, Anssi

2016-11-22

Protective effects have been suggested for digoxin against prostate cancer risk. However, few studies have evaluated the possible effects on prostate cancer-specific survival. We studied the association between use of digoxin or beta-blocker sotalol and prostate cancer-specific survival as compared with users of other antiarrhythmic drugs in a retrospective cohort study. Our study population consisted of 6537 prostate cancer cases from the Finnish Randomized Study of Screening for Prostate Cancer diagnosed during 1996-2009 (485 digoxin users). The median exposure for digoxin was 480 DDDs (interquartile range 100-1400 DDDs). During a median follow-up of 7.5 years after diagnosis, 617 men (48 digoxin users) died of prostate cancer. We collected information on antiarrhythmic drug purchases from the national prescription database. Both prediagnostic and postdiagnostic drug usages were analysed using the Cox regression method. No association was found for prostate cancer death with digoxin usage before (HR 1.00, 95% CI 0.56-1.80) or after (HR 0.81, 95% CI 0.43-1.51) prostate cancer diagnosis. The results were also comparable for sotalol and antiarrhythmic drugs in general. Among men not receiving hormonal therapy, prediagnostic digoxin usage was associated with prolonged prostate cancer survival (HR 0.20, 95% CI 0.05-0.86). No general protective effects against prostate cancer were observed for digoxin or sotalol usage.

[Chemical castration using a depot LHRH-agonist as a palliative therapy concept in prostatic carcinoma--clinical, endocrinological and experimental studies].

PubMed

Kuber, W; Treu, T; Kratzik, C; Girsch, E; Zeillinger, R; Spona, J

1990-11-09

79 patients with locally advanced and/or metastatic prostate cancer were treated by means of a biodegradeable depot formulation of the luteinizing hormone releasing hormone analogue Goserelin (Zoladex). All patients received 3.6 mg depot Goserelin (Zoladex 3.6 mg implantate) subcutaneously into the anterior abdominal wall at 4 weekly intervals. The average time of observation was 24.2 months. The best objective response rate was found in 62%. Serum testosterone levels initially increased after the first depot injection and then decreased ultimately to castrate range (less than 0.6 ng/ml) between day 15 and day 27 (median 21) in the majority of patients. Castrate testosterone levels were still found 48 months after the start of treatment with depot Goserelin. 6 months after institution of treatment in 66.7% of cases evident signs of histological regression were found in the primary tumour tissue. Adenocarcinoma presented with a highly significantly better response pattern than anaplastic carcinoma. In animal experiments a single dose of 1 mg depot Goserelin was administered to adult male rats and the effect on serum testosterone levels and target organs (testes and ventral prostate) were investigated. Mean testosterone levels (mean = 0.31 ng/ml) decreased to castrate range (less than 0.3 ng/ml). 4 weeks after depot injection weight of the testes and prostate weight were significantly reduced. However 8 weeks after administration of 1 mg depot Goserelin there was no significant between the control group and the treated group. We conclude that the depot formulation of Goserelin (Zoladex) is effective, simple, practicable and safe in the treatment of advanced prostatic cancer. Current clinical studies are confirming the importance of reversible medical castration by LHRH agonists before radical prostatectomy.

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist*

PubMed Central

Song, Chin-Hee; Yang, Su Hui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Keesook

2012-01-01

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4–2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer. PMID:22798067

ONC201 Targets AR and AR-V7 Signaling, Reduces PSA, and Synergizes with Everolimus in Prostate Cancer.

PubMed

Lev, Avital; Lulla, Amriti R; Ross, Brian C; Ralff, Marie D; Makhov, Petr B; Dicker, David T; El-Deiry, Wafik S

2018-05-01

Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754-66. ©2018 AACR . ©2018 American Association for Cancer

Comorbidity, Use of Common Medications, and Risk of Early Death in Patients with Localized or Locally Advanced Prostate Cancer

PubMed Central

Nieder, Carsten; Dalhaug, Astrid; Pawinski, Adam; Aandahl, Gro; Norum, Jan

2011-01-01

In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores ≥5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score ≥5 (univariate analysis). However, medication use was not an independent factor as all patients with age-adjusted CCI score ≥5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score ≥5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis. PMID:21666987

Hormonal induction of transfected genes depends on DNA topology.

PubMed Central

Piña, B; Haché, R J; Arnemann, J; Chalepakis, G; Slater, E P; Beato, M

1990-01-01

Plasmids containing the hormone regulatory element of mouse mammary tumor virus linked to the thymidine kinase promoter of herpes simplex virus and the reporter gene chloramphenicol acetyltransferase of Escherichia coli respond to glucocorticoids and progestins when transfected into appropriate cells. In the human mammary tumor cell line T47D, the response to progestins, but not to glucocorticoids, is highly dependent on the topology of the transfected DNA. Although negatively supercoiled plasmids respond optimally to the synthetic progestin R5020, their linearized counterparts exhibit markedly reduced progestin inducibility. This is not due to changes in the efficiency of DNA transfection, since the amount of DNA incorporated into the cell nucleus is not significantly dependent on the initial topology of the plasmids. In contrast, cotransfection experiments with glucocorticoid receptor cDNA in the same cell line show no significant influence of DNA topology on induction by dexamethasone. A similar result was obtained with fibroblasts that contain endogenous glucocorticoid receptors. When the distance between receptor-binding sites or between the binding sites and the promoter was increased, the dependence of progestin induction on DNA topology was more pronounced. In contrast to the original plasmid, these constructs also revealed a similar topological dependence for induction by glucocorticoids. The differential influence of DNA topology is not due to differences in the affinity of the two hormone receptors for DNA of various topologies, but probably reflects an influence of DNA topology on the interaction between different DNA-bound receptor molecules and between receptors and other transcription factors. Images PMID:2153920

Association of microRNA-21 expression with clinicopathological characteristics and the risk of progression in advanced prostate cancer patients receiving androgen deprivation therapy.

PubMed

Guan, Yangbo; Wu, You; Liu, Yifei; Ni, Jian; Nong, Shaojun

2016-08-01

Despite androgen deprivation therapy (ADT) remains the mainstay therapy for advanced prostate cancer (PCa), the patients have widely variable durations of response to ADT. Unfortunately, there is limited knowledge of pre-treatment prognostic factors for response to ADT. Recently, microRNA-21 (miR-21) has been reported to play an important role in development of castration resistance of CaP. However, little is known about the expression of miR-21 in advanced PCa biopsy tissues, and data on its potential predictive value in advanced PCa are completely lacking. In this study, paraffin-embedded prostate carcinoma tissues obtained by needle biopsy from 85 advanced PCa patients were evaluated for the expression levels of miR-21 by quantitative real-time PCR (qRT-PCR). In situ hybridization (ISH) analysis was performed to further confirm the qRT-PCR results. Kaplan-Meier analysis and Cox proportional hazards regression models were performed to investigate the correlation between miR-21 expression and time to progression of advanced PCa patients. Compared with adjacent non-cancerous prostate tissues, the expression level of miR-21 was significantly increased in PCa tissues (PCa vs. non-cancerous prostate: 1.3273 ± 0.3207 vs. 0.9970 ± 0.2054, P < 0.001). By and large, in ISH analysis miR-21 was expressed at a higher level in tumor areas than in adjacent non-cancerous areas. Additionally, PCa patients with higher expression of miR-21 were significantly more likely to be of high Gleason score and high clinical stage (P < 0.05). There was no significant association between miR-21 expression and the initial prostate-specific antigen (PSA) level or age at diagnosis. Moreover, Kaplan-Meier survival analysis found that PCa patients with high miR-21 expression have shorter progression-free survival than those with low miR-21 expression. Furthermore, Multivariate Cox analysis revealed both miR-21 expression status (P = 0.040) and clinical stage (P = 0

New Prostate Cancer Treatment Target

Cancer.gov

Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

Prostate ultrasound--for urologists only?

PubMed

Frauscher, Ferdinand; Gradl, Johann; Pallwein, Leo

2005-11-23

The value of ultrasound (US) in the diagnosis of prostate cancer has dramatically increased in the past decade. This is mainly related to the increasing incidence of prostate cancer, the most common cancer in men and one of the most important causes of death from cancer in men. The value of conventional gray-scale US for prostate cancer detection has been extensively investigated, and has shown a low sensitivity and specificity. Therefore conventional gray-scale US is mainly used by urologists for guiding systematic prostate biopsies. With the development of new US techniques, such as color and power Doppler US, and the introduction of US contrast agents, the role of US for prostate cancer detection has dramatically changed. Advances in US techniques were introduced to further increase the value of US contrast agents. Although most of these developments in US techniques, which use the interaction of the contrast agent with the transmitted US waves, are very sensitive for the detection of microbubbles, they are mostly unexplored, in particular for prostate applications. Early reports of contrast-enhanced US investigations of blood flow of the prostate have shown that contrast-enhanced US adds important information to the conventional gray-scale US technique. Furthermore, elastography or 'strain imaging' seems to have great potential in prostate cancer detection. Since these new advances in US are very sophisticated and need a long learning curve, radiologists, who are overall better trained with these new US techniques, will play a more important role in prostate cancer diagnosis. Current trends show that these new US techniques may allow for targeted biopsies and therefore replace the current 'gold standard' for prostate cancer detection--the systematic biopsy. Consequently the use of these new US techniques for the detection and clinical staging of prostate cancer is promising. However, future clinical trials will be needed to determine if the promise of these new

An in-advance stable isotope labeling strategy for relative analysis of multiple acidic plant hormones in sub-milligram Arabidopsis thaliana seedling and a single seed.

PubMed

Sun, Xiaohong; Ouyang, Yue; Chu, Jinfang; Yan, Jing; Yu, Yan; Li, Xiaoqiang; Yang, Jun; Yan, Cunyu

2014-04-18

A sensitive and reliable in-advance stable isotope labeling strategy was developed for simultaneous relative quantification of 8 acidic plant hormones in sub-milligram amount of plant materials. Bromocholine bromide (BETA) and its deuterated counterpart D9-BETA were used to in-advance derivatize control and sample extracts individually, which were then combined and subjected to solid-phase extraction (SPE) purification followed by UPLC-MS/MS analysis. Relative quantification of target compounds was obtained by calculation of the peak area ratios of BETA/D9-BETA labeled plant hormones. The in-advance stable isotope labeling strategy realized internal standard-based relative quantification of multiple kinds of plant hormones independent of availability of internal standard of every analyte with enhanced sensitivity of 1-3 orders of magnitude. Meanwhile, the in-advance labeling contributes to higher sample throughput and more reliability. The method was successfully applied to determine 8 plant hormones in 0.8mg DW (dry weight) of seedlings and 4 plant hormones from single seed of Arabidopsis thaliana. The results show the potential of the method in relative quantification of multiple plant hormones in tiny plant tissues or organs, which will advance the knowledge of the crosstalk mechanism of plant hormones. Copyright © 2014 Elsevier B.V. All rights reserved.

Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

PubMed Central

Mason, Malcolm D.; Parulekar, Wendy R.; Sydes, Matthew R.; Brundage, Michael; Kirkbride, Peter; Gospodarowicz, Mary; Cowan, Richard; Kostashuk, Edmund C.; Anderson, John; Swanson, Gregory; Parmar, Mahesh K.B.; Hayter, Charles; Jovic, Gordana; Hiltz, Andrea; Hetherington, John; Sathya, Jinka; Barber, James B.P.; McKenzie, Michael; El-Sharkawi, Salah; Souhami, Luis; Hardman, P.D. John; Chen, Bingshu E.; Warde, Padraig

2015-01-01

Purpose We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. Patients and Methods NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. Results One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. Conclusion This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer. PMID:25691677

Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

PubMed

Friedlander, Terence W; Roy, Ritu; Tomlins, Scott A; Ngo, Vy T; Kobayashi, Yasuko; Azameera, Aruna; Rubin, Mark A; Pienta, Kenneth J; Chinnaiyan, Arul; Ittmann, Michael M; Ryan, Charles J; Paris, Pamela L

2012-02-01

Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. ©2012 AACR.

A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

NASA Astrophysics Data System (ADS)

Portz, Travis; Kuang, Yang; Nagy, John D.

2012-03-01

Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

Clinical Usefulness of the Histoculture Drug Response Assay for Prostate Cancer and Benign Prostate Hypertrophy (BPH).

PubMed

Hoffman, Robert M

2018-01-01

The histoculture drug response assay (HDRA) has been adapted to determine androgen sensitivity in Gelfoam histoculture of human benign prostatic tissue as well as prostate cancer. Gelfoam histoculture was used to measure androgen-independent and androgen-dependent growth of benign and malignant prostate tissue. The androgen-sensitivity index was significantly higher in 23 paired specimens of prostate cancer compared to benign prostate hypertrophy (BPH). Genistein decreased the androgen-sensitivity index of BPH and prostate cancer in Gelfoam ® histoculture in a dose-dependent manner.

Trends in initial management of prostate cancer in New Hampshire.

PubMed

Ingimarsson, Johann P; Celaya, Maria O; Laviolette, Michael; Rees, Judy R; Hyams, Elias S

2015-06-01

Prostate cancer management strategies are evolving with increased understanding of the disease. Specifically, there is emerging evidence that "low-risk" cancer is best treated with observation, while localized "high-risk" cancer requires aggressive curative therapy. In this study, we evaluated trends in management of prostate cancer in New Hampshire to determine adherence to evidence-based practice. From the New Hampshire State Cancer Registry, cases of clinically localized prostate cancer diagnosed in 2004-2011 were identified and classified according to D'Amico criteria. Initial treatment modality was recorded as surgery, radiation therapy, expectant management, or hormone therapy. Temporal trends were assessed by Chi-square for trend. Of 6,203 clinically localized prostate cancers meeting inclusion criteria, 34, 30, and 28% were low-, intermediate-, and high-risk disease, respectively. For low-risk disease, use of expectant management (17-42%, p < 0.001) and surgery (29-39%, p < 0.001) increased, while use of radiation therapy decreased (49-19 %, p < 0.001). For intermediate-risk disease, use of surgery increased (24-50%, p < 0.001), while radiation decreased (58-34%, p < 0.001). Hormonal therapy alone was rarely used for low- and intermediate-risk disease. For high-risk patients, surgery increased (38-47%, p = 0.003) and radiation decreased (41-38%, p = 0.026), while hormonal therapy and expectant management remained stable. There are encouraging trends in the management of clinically localized prostate cancer in New Hampshire, including less aggressive treatment of low-risk cancer and increasing surgical treatment of high-risk disease.

Androgen biosynthesis in castration-resistant prostate cancer

PubMed Central

Penning, Trevor M

2014-01-01

Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination. PMID:24829267

Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer.

PubMed

Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley E; Long, Henry W; Freedman, Matthew L; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L

2017-09-11

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. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

Thyroid hormone transporters in health and disease: advances in thyroid hormone deiodination.

PubMed

Köhrle, Josef

2007-06-01

Thyroid hormone metabolism by the three deiodinase selenoproteins -- DIO1, DIO2, and DIO3 -- regulates the local availability of various iodothyronine metabolites and thus mediates their effects on gene expression, thermoregulation, energy metabolism, and many key reactions during the development and maintenance of an adult organism. Circulating serum levels of thyroid hormone and thyroid-stimulating hormone, used as a combined indicator of thyroid hormone status, reflect a composite picture of: thyroid secretion; tissue-specific production of T(3) by DIO1 and DIO2 activity, which both contribute to circulating levels of T(3); and degradation of the prohormone T4, of the thyromimetically active T(3), of the inactive rT(3), of other iodothyronines metabolites with a lower iodine content and of thyroid hormone conjugates. Degradation reactions are catalyzed by either DIO1 or DIO3. Aberrant expression of individual deiodinases in disease, single nucleotide polymorphisms in their genes, and novel regulators of DIO gene expression (such as bile acids) provide a more complex picture of the fine tuning and the adaptation of systemic and local bioavailability of thyroid hormones.

Targeted Elimination of PCDH-PC Expressing Prostate Cancer Cells for Control of Hormone-Resistant Prostate Cancer

DTIC Science & Technology

2008-11-01

or antisense oligonucleotides ( ASOs ) might be useful in preventing the development of castration- recurrent prostate cancer in prostate cancer...patients. To this end, we have created functional shRNA vectors and ASOs capable of suppressing PCDH-PC expression and we have also created a monoclonal...electrophoresed on an SDS-PAGE gel and blotted onto a filter. The filter was probed with an anti-myc antibody. The levels of myc-tagged PCDH-PC protein

Targeted Elimination of PCDH-PC Expressing Prostate Cancer Cells for Control of Hormone-Resistant Prostate Cancer

DTIC Science & Technology

2009-11-01

expression knockout by shRNAs or antisense oligonucleotides ( ASOs ) might be useful in preventing the development of castration-recurrent prostate...cancer in prostate cancer patients. To this end, we have created functional shRNA vectors and ASOs capable of suppressing PCDH-PC expression and we have...containing PCDH-PC cDNA. Cell extracts were prepared 48 hrs after co-transfection and were electrophoresed on an SDS-PAGE gel and blotted onto a

How Precisely Can Prostate Cancer Be Managed?

PubMed Central

2016-01-01

Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2-ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy. Oncotype DX, Prolaris, the biopsy-based Decipher prostate cancer test, and ProMark may improve predictive risk stratification in addition to the traditional Gleason score and tumor stage. Decipher and Prolaris may predict biochemical recurrence and metastasis after radical prostatectomy and possibly help identify patients who need adjuvant therapy. Androgen receptor splice variant 7 appears effective in guiding the selection of second hormonal manipulation with abiraterone or enzalutamide versus chemotherapy when treating metastatic castration-resistant prostate cancer. PMID:27915475

Screening for prostate cancer

NASA Technical Reports Server (NTRS)

Weirich, Stephen A.

1993-01-01

Despite recent advances in both the survival and cure rates for many forms of cancer, unfortunately the same has not been true for prostate cancer. In fact, the age-adjusted death rate from prostate cancer has not significantly improved since 1949, and prostate cancer remains the most common cancer in American men, causing the second highest cancer mortality rate. Topics discussed include the following: serum testosterone levels; diagnosis; mortality statistics; prostate-sppecific antigen (PSA) tests; and the Occupational Medicine Services policy at LeRC.

Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Cheng, Heather H; Abida, Wassim; Ellis, Leigh; Harshman, Lauren C; Spratt, Daniel E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2017-11-01

The 2017 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate Cancer," was held in Carlsbad, California from June 14-17, 2017. The CHPCA is an annual scientific conference hosted by the Prostate Cancer Foundation (PCF) that is uniquely designed to produce extensive and constructive discussions on the most urgent and impactful topics concerning research into the biology and treatment of metastatic prostate cancer. The 2017 CHPCA Meeting was the 5th meeting in this annual series and was attended by 71 investigators focused on prostate cancer and a variety of other fields including breast and ovarian cancer. The discussions at the meeting were concentrated on topics areas including: mechanisms and therapeutic approaches for molecular subclasses of castrate resistant prostate cancer (CRPC), the epigenetic landscape of prostate cancer, the role of DNA repair gene mutations, advancing the use of germline genetics in clinical practice, radionuclides for imaging and therapy, advances in molecular imaging, and therapeutic strategies for successful use of immunotherapy in advanced prostate cancer. This article reviews the presentations and discussions from the 2017 CHPCA Meeting in order to disseminate this knowledge and accelerate new biological understandings and advances in the treatment of patients with metastatic prostate cancer. © 2017 Wiley Periodicals, Inc.

Robotic high-intensity focused ultrasound (rHIFU) for the prostate cancer treatment

NASA Astrophysics Data System (ADS)

Solovov, Vyacheslav; Shaplygin, Leonid; Vozdvizhenskiy, Mikhail

2012-11-01

Introduction & Objectives: rHIFU shows a successful treatment for localized prostate cancer (PC). Here we explored the effectiveness of the rHIFU treatment for the prostate cancer, hormone-resistant prostate cancer (HRPC) and failure after external beam radiotherapy (EBRT) and radical prostatectomy (RPE). Materials & Methods: 748 patients were treated in our center between Sep 2007 - February 2012: 137 - hormone-resistance (median time before hormone-resistance 25 months), 286 - received neoadjuvant hormone therapy 6 months, 293 - no treatment before HIFU, 32 - after the EBRT failure. 667 patients underwent TURP+rHIFU, 81 only rHIFU (volume prostate <40cc). Mean follow-up is 38 months (range 3-52). All patients were divided into 3 groups: low risk progression (Gleason <7, stage T1-2N0M0, PSA<20, n= 465), high risk progression - (Gleason ≤9, stage T2-3N0M0, PSA <60, n= 251), after EBRT and RPE failure (n= 39). The mean age of the whole group of patients were 70 (52-89) years, mean prostate volume - 39 (5,5-108) cc. Results: Median PSA level 12 months after rHIFU treatment were 0,04 (0-2,24) ng/ml - low risk group, for high risk group - 0,5 (0-48,4) ng/ml, with failure after EBRT and RPE- 0,5 (0-3,2) ng/ml; 36 months after rHIFU treatment were 0,5 (0,02-3,6) ng/ml - low risk group, for high risk group - 3,2 (0-21,38) ng/ml, with failure after EBRT and RPE - 1,7 (0-9,8) ng/ml. Patients with low risk had 4,5% of progression, with high risk PC - 25%, with failure after EBRT and RPE - 19,6%. Kaplan-Meir analyses of the total group indicated that the risk of progression after 1 year follow-up was 10%, the risk of progression was 23% after 4 years of follow-up. Complications: incontinence I - 17,5%, incontinence II - 7,7%, stricture - 18,2%, fistula - 0,3 %. Conclusions: Our experience shows that rHIFU ablation is safe, minimally invasive, effective treatment with moderate side effects for the PC, hormone-resistant prostate cancer, rHIFU also may be used as a salvage

A Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment

DTIC Science & Technology

2015-10-01

as an oral contraceptive [6, 7]. Recently, its anti-cancer activity has been reported against advanced breast cancer [8] and head and neck squamous...profile of Centchroman--a new post-coital contraceptive . Indian J Exp Biol, 1977. 15(12): p. 1144-50. 7. Misra, N.C., et al., Centchroman--a non-steroidal... contraceptive and for the management of hormone-related clinical disorders. Med Res Rev, 2001. 21(4): p. 302-47. 11. Jaggi, M., et al., Bryostatin 1 modulates

Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha-dependent apoptosis.

PubMed

Giampietri, Claudia; Petrungaro, Simonetta; Padula, Fabrizio; D'Alessio, Alessio; Marini, Elettra Sara; Facchiano, Antonio; Filippini, Antonio; Ziparo, Elio

2012-11-01

TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules for 18, 24 and 48 h. Autophagy was assessed via LC3 Western blot analysis; propidium iodide and TUNEL stainings followed by flow cytometry or caspase-8 and caspase-3 activation assays were performed to evaluate apoptosis. TNF-alpha-induced apoptosis was potentiated by 3-methyladenine in the androgen-responsive LNCaP cells, whereas no effect was observed in the androgen-insensitive PC3 cells. Interestingly such pro-apoptosis effect in LNCaP cells was associated with reduced c-Flip levels through proteasomal degradation via increased reactive oxygen species production and p38 activation; such c-Flip reduction was reversed in the presence of either the proteasome inhibitor MG132 or the reactive oxygen species scavenger N-acetyl-cysteine. Conversely in PC3 but not in LNCaP cells, rapamycin stimulated TNF-alpha-dependent apoptosis; such effect was associated with reduced c-Flip promoter activity and FoxO3a activation. We conclude that TNF-alpha-induced apoptosis may be potentiated, in prostate cancer epithelial cells, through autophagy modulators. Increased sensitivity to TNF-alpha-dependent apoptosis correlates with reduced c-Flip levels which are consequent to a post-transcriptional and a transcriptional mechanism in LNCaP and PC3 cells respectively.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed Central

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-01-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells. PMID:2548207

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

Open, multi-center, phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer.

PubMed

Kao, Chien-Chang; Chang, Yen-Hwa; Wu, Tony; Sun, Guang-Huan; Yu, Dah-Shyong; Chang, Sun-Yran; Cha, Tai-Lung

2012-06-01

To evaluate the efficacy and safety of administering a 3-month formulation of triptorelin as part of disease management of Taiwanese men with advanced adenocarcinoma of the prostate. Patients with newly diagnosed, locally advanced, or metastatic adenocarcinoma of the prostate were enrolled in our study, after informed consent was obtained. All patients received bicalutamide 50 mg daily for 28 days, starting 7 days before the first injection of triptorelin. A dosage of 11.25 mg triptorelin was injected on Day 0 (baseline) and repeated on Day 90. Prostate-specific antigen (PSA) and testosterone concentrations were measured on Days 90 and 180. A total of 41 patients were enrolled, with a median age of 78 (57-92) years, and a baseline median PSA of 122.69 ng/mL. One patient dropped out of the study, one was excluded in the fourth month due to a protocol violation, and one died 4 months after initiation of treatment as a result of disease progression. In total, 40 men were eligible for Day 90 and 38 men for Day 180 analysis. On Day 90, 97.5% of men had reached castration testosterone concentration ≤0.5 ng/mL, and all men had reached this concentration on Day 180. Serum PSA concentration declined to 10.40 ± 23.42 ng/mL on Day 90 (p = 0.0126) and 11.61 ± 23.93 ng/mL on Day 180 (p = 0.0172). The most frequently seen adverse event was gastrointestinal disturbance, including abdominal pain, diarrhea and constipation. Generally, adverse events were mild and patient manageable. Triptorelin 11.25 mg is effective in achieving medical castration and lowering PSA concentrations and can maintain its medicinal effect for at least 90 days in Taiwanese men with advanced prostate cancer. This suggests that it can be an effective treatment for advanced prostatic cancer. Copyright © 2012. Published by Elsevier B.V.

The impact of transcription on metabolism in prostate and breast cancers.

PubMed

Poulose, Ninu; Mills, Ian G; Steele, Rebecca E

2018-05-14

Metabolic dysregulation is regarded as an important driver in cancer development and progression. The impact of transcriptional changes on metabolism have been intensively studied in hormone-dependent cancers, and in particular in prostate and breast cancer. These cancers have strong similarities in the function of important transcriptional drivers, such as the estrogen and androgen receptor, at the level of dietary risk and epidemiology, genetics and therapeutically. In this review we will focus on the function of these nuclear hormone receptors and their downstream impact on metabolism, with a particular focus on lipid metabolism. We go on to discuss how lipid metabolism remains dysregulated as the cancers progress. We conclude by discussing the opportunities that this presents for drug repurposing, imaging and the development and testing of new therapeutics and treatment combinations.

Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer.

PubMed

Eymerit-Morin, Caroline; Zidane, Merzouka; Lebdai, Souhil; Triau, Stéphane; Azzouzi, Abdel Rahmene; Rousselet, Marie-Christine

2013-10-01

Low-risk prostate adenocarcinoma is classically managed either with active surveillance or radical therapy (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy proposed as an alternative approach for localized, low-volume, and low-Gleason score (≤6) carcinomas. We report histological modifications observed in prostate biopsies of 56 patients, performed 6 months after VTP using the photosensitizer TOOKAD® Soluble (WST11) and low-energy laser administered in the tumor area transperineally by optic fibers. In 53 patients, we observed sharply demarcated hyaline fibrotic scars, with or without rare atrophic glands, sometimes reduced to corpora amylacea surrounded by giant multinuclear macrophages. Mild chronic inflammation, hemosiderin, and coagulative necrosis were also observed. When residual cancer was present in a treated lobe (17 patients), it was always located outside the scar, most often close to the prostate capsule, and it showed no therapy-related modification. Histopathological interpretation of post-WST11 VTP prostate biopsies was straightforward, in contrast with that of prostate biopsies after radio or hormonal therapy, which introduces lesions difficult to interpret. VTP resulted in complete ablation of cancer in the targeted area.

PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade.

PubMed

Özgür, Emre; Celik, Ayca Iribas; Darendeliler, Emin; Gezer, Ugur

2017-07-01

Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR + cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3-silenced and/or AR-blocked cells. PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR + cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Liquid biopsy: ready to guide therapy in advanced prostate cancer?

PubMed

Hegemann, Miriam; Stenzl, Arnulf; Bedke, Jens; Chi, Kim N; Black, Peter C; Todenhöfer, Tilman

2016-12-01

The identification of molecular markers associated with response to specific therapy is a key step for the implementation of personalised treatment strategies in patients with metastatic prostate cancer. Only in a low proportion of patients biopsies of metastatic tissue are performed. Circulating tumour cells (CTC), cell-free DNA (cfDNA) and RNA offer the potential for non-invasive characterisation of disease and molecular stratification of patients. Furthermore, a 'liquid biopsy' approach permits longitudinal assessments, allowing sequential monitoring of response and progression and the potential to alter therapy based on observed molecular changes. In prostate cancer, CTC enumeration using the CellSearch© platform correlates with survival. Recent studies on the presence of androgen receptor (AR) variants in CTC have shown that such molecular characterisation of CTC provides a potential for identifying patients with resistance to agents that inhibit the androgen signalling axis, such as abiraterone and enzalutamide. New developments in CTC isolation, as well as in vitro and in vivo analysis of CTC will further promote the use of CTC as a tool for retrieving molecular information from advanced tumours in order to identify mechanisms of therapy resistance. In addition to CTC, nucleic acids such as RNA and cfDNA released by tumour cells into the peripheral blood contain important information on transcriptomic and genomic alterations in the tumours. Initial studies have shown that genomic alterations of the AR and other genes detected in CTC or cfDNA of patients with castration-resistant prostate cancer correlate with treatment outcomes to enzalutamide and abiraterone. Due to recent developments in high-throughput analysis techniques, it is likely that CTC, cfDNA and RNA will be an important component of personalised treatment strategies in the future. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer.

PubMed

Brägelmann, Johannes; Klümper, Niklas; Offermann, Anne; von Mässenhausen, Anne; Böhm, Diana; Deng, Mario; Queisser, Angela; Sanders, Christine; Syring, Isabella; Merseburger, Axel S; Vogel, Wenzel; Sievers, Elisabeth; Vlasic, Ignacija; Carlsson, Jessica; Andrén, Ove; Brossart, Peter; Duensing, Stefan; Svensson, Maria A; Shaikhibrahim, Zaki; Kirfel, Jutta; Perner, Sven

2017-04-01

Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches. Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities ( n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer ( n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq. Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19 In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro , inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion. Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer. Clin Cancer Res; 23(7); 1829-40. ©2016 AACR . ©2016 American Association for Cancer Research.

The Influence of Prostate Volume on Outcome After High-Dose-Rate Brachytherapy Alone for Localized Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Le, Hien, E-mail: hien.le@health.sa.gov.au; Rojas, Ana; Alonzi, Roberto

2013-10-01

Objective: To determine whether late genitourinary toxicity, biochemical control of prostate cancer, and dosimetric parameters in patients with large prostate glands is different from those variables in men with smaller glands after treatment with high-dose-rate brachytherapy alone (HDR-BT). Methods: From November 2003 to July 2009, 164 patients with locally advanced prostate carcinoma were sequentially enrolled and treated with 34 or 36 Gy in 4 fractions and 31.5 Gy in 3 fractions of {sup 192}Ir HDR-BT alone. The median follow-up time was 71 months. Gland size was not considered in the selection criteria for this study. Estimates of freedom from biochemicalmore » relapse (FFbR) and late morbidity, stratified by median clinical target volume (CTV), were obtained, and differences were compared. Results: The median CTV volume was 60 cc (range, 15-208 cc). Dose–volume parameters D90 and V100 (ie, minimum dose to 90% of the prostate volume and volume receiving 100% of the prescribed isodose) achieved in patients with glands ≥60 cc were not significantly different from those with glands <60 cc (P≥.2). Nonetheless, biochemical control in patients with larger CTV was significantly higher (91% vs 78% at 6 years; P=.004). In univariate and multivariate analysis, CTV was a significant predictor for risk of biochemical relapse. This was not at the expense of an increase in either moderate (P=.6) or severe (P=.3) late genitourinary toxicity. The use of hormonal therapy was 17% lower in the large gland group (P=.01). Conclusions: Prostate gland size does not affect dosimetric parameters in HDR-BT assessed by D90 and V100. In patients with larger glands, a significantly higher biochemical control of disease was observed, with no difference in late toxicity. This improvement cannot be attributed to differences in dosimetry. Gland size should not be considered in the selection of patients for HDR-BT.« less

A Phase II Immunotherapeutic Trial: Combination Androgen Ablative Therapy Treatment for Advanced Prostate Cancer

DTIC Science & Technology

2008-03-01

two study statisticians; d) the filing of an investigator IND with the FDA; e) procurement of local IRB approvals; f) procurement of FDA-approval to...compromising the interpretation of outcome data pertaining to the treatment of patients with local or advanced prostate cancer receiving treatment on...patients prior treatment (radiation or cryotherapy ) • 1 patient taking Saw Palmetto (before criteria changed) • 5 patients taking Proscar/Avodart • 2

Estrogen Metabolism and Prostate Cancer Risk: A Prospective Study

DTIC Science & Technology

2005-05-01

growth hormone concentrations in blood and the risk for prostate cancer: A case- control study. Prostate. 2005- Jan 21 ( Electronic publication ahead... cigarette smoking status, education, body mass index (BMI), and waist to hip ratio (WHRATIO). The beverage specific analyses were further mutually adjusted...affecting the metabolism of detoxification enzymes, impairment of immune system and depression of DNA repair enzymes (31). It remains unclear to what

Mortality among men with locally advanced prostate cancer managed with noncurative intent: a nationwide study in PCBaSe Sweden.

PubMed

Akre, Olof; Garmo, Hans; Adolfsson, Jan; Lambe, Mats; Bratt, Ola; Stattin, Pär

2011-09-01

There are limited prognostic data for locally advanced prostate cancer PCa to guide in the choice of treatment. To assess mortality in different prognostic categories among men with locally advanced PCa managed with noncurative intent. We conducted a register-based nationwide cohort study within the Prostate Cancer DataBase Sweden. The entire cohort of locally advanced PCa included 14 908 men. After the exclusion of 2724 (18%) men treated with curative intent, 12 184 men with locally advanced PCa either with local clinical stage T3 or T4 or with T2 with serum levels of prostate-specific antigen (PSA) between 50 and 99 ng/ml and without signs of metastases remained for analysis. We followed up the patient cohort in the Cause of Death Register for ≤ 11 yr and assessed cumulative incidence of PCa -specific death stratified by age and clinical characteristics. The PCa -specific mortality at 8 yr of follow-up was 28% (95% confidence interval [CI], 25-32%) for Gleason score (GS) 2-6, 41% (95% CI, 38-44%) for GS 7, 52% (95% CI, 47-57%) for GS 8, and 64% (95% CI, 59-69%) for GS 9-10. Even for men aged >85 yr at diagnosis with GS 8-10, PCa was a major cause of death: 42% (95% CI, 37-47%). Men with locally advanced disease and a PSA<4 ng/ml at diagnosis were at particularly increased risk of dying from PCa. One important limitation is the lack of bone scans in 42% of the patient cohort, but results remained after exclusion of patients with unknown metastasis status. The PCa-specific mortality within 8 yr of diagnosis is high in locally advanced PCa, suggesting undertreatment, particularly among men in older age groups. Our results underscore the need for more studies of treatment with curative intent for locally advanced tumors. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A biological approach to characterizing exposure to metalworking fluids and risk of prostate cancer (United States).

PubMed

Agalliu, Ilir; Eisen, Ellen A; Kriebel, David; Quinn, Margaret M; Wegman, David H

2005-05-01

Prostate cancer is hormone-related and chemicals that interfere with hormones may contribute to carcinogenesis. In a cohort of autoworkers we characterized exposure to metalworking fluids (MWF) into age windows with homogenous biological risk for prostate cancer, and examined exposure-response relationships using semi-parametric modeling. Incident cases (n=872) were identified via Michigan cancer registry from 1985 through 2000. Controls were selected using incidence-density sampling, 5:1 ratio. Using a hormonal-based model, exposure was accumulated in three windows: (1) late puberty, (2) adulthood, and (3) middle age. We used penalized splines to model risk as a smooth function of exposure, and controlled for race and calendar year of diagnosis in a Cox model. Risk of prostate cancer linearly increased with exposure to straight MWF in the first window, with a relative risk of 2.4 per 10 mg/m(3)-years. Autoworkers exposed to MWF at a young age also had an increased risk associated with MWF exposure incurred later in life. For soluble MWF there was a slightly increased risk in the third window. Exposure characterization based on a hormonal model identified heightened risk with early age of exposure to straight MWF. Results also support a long latency period for exposure related prostate cancer.

LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d Serve as Models for Evaluating Cancer Therapeutics.

PubMed

Nguyen, Holly M; Vessella, Robert L; Morrissey, Colm; Brown, Lisha G; Coleman, Ilsa M; Higano, Celestia S; Mostaghel, Elahe A; Zhang, Xiaotun; True, Lawrence D; Lam, Hung-Ming; Roudier, Martine; Lange, Paul H; Nelson, Peter S; Corey, Eva

2017-05-01

Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long-term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of biology of this malignancy and to evaluate new agents that might provide effective treatment. Our objective was to establish and characterize patient-derived xenografts (PDXs) from advanced prostate cancer (PC) for investigation of biology and evaluation of new treatment modalities. Samples of advanced PC obtained from primary prostate cancer obtained at surgery or from metastases collected at time of death were implanted into immunocompromised mice to establish PDXs. Established PDXs were propagated in vivo. Genomic, transcriptomic, and STR profiles were generated. Responses to androgen deprivation and docetaxel in vivo were characterized. We established multiple PDXs (LuCaP series), which represent the major genomic and phenotypic features of the disease in humans, including amplification of androgen receptor, PTEN deletion, TP53 deletion and mutation, RB1 loss, TMPRSS2-ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss. The PDX models also exhibit variation in intra-tumoral androgen levels. Our in vivo results show heterogeneity of response to androgen deprivation and docetaxel, standard therapies for advanced PC, similar to the responses of patients to these treatments. The LuCaP PDX series reflects the diverse molecular composition of human castration-resistant PC and allows for hypothesis-driven cause-and-effect studies of mechanisms underlying treatment response and resistance. Prostate 77: 654-671, 2017. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.

Potential efficacy of some african plants in benign prostatic hyperplasia and prostate cancer.

PubMed

Russo, Giorgio I; Cimino, Sebastiano; Salamone, Costanza; Madonia, Massimo; Favilla, Vincenzo; Castelli, Tommaso; Morgia, Giuseppe

2013-10-01

Traditional medicine is very popular in Africa and it is considered as an alternative form of health care. Plants and vegetables used in folk and traditional medicine have gained wide acceptance as one of the main sources of prophylactic and chemopreventive drug discovery and this is due to the evidence of particular biological and biochemical characteristics of each plants extracts. The role of these compounds in urological field may be explained by the antiinflammatory effect through interference with prostaglandin metabolism, alteration of lipid peroxidation, direct inhibition of prostate growth and moreover through an antiandrogenic or antiestrogenic effect and a decrease of the availability of sex hormone-binding globulin. Since Benign Prostatic Hyperplasia and Prostate Cancer are two of the most diffuse diseases of aging male and considering that standard medical therapy is accompanied with different side effects, the emerging use of African plants may be justified. This review takes a look at some African plants extracts properties and their relative urological application. Different biomolecular mechanisms of action are promising, suggesting a real application in reducing prostate cells proliferation.

The prevention of benign prostatic hyperplasia (bph).

PubMed

Roper, W G

2017-03-01

Barry Marshall and Robin Warren were the first to show that the chronic diseases (gastric ulcer and chronic gastritis) were caused by an infection (Helicobacter pylori). The chronic disease benign prostatic hyperplasia belongs to the same ilk, except that the infection process is much more subtle and complex. The enzyme Phospholipase D (PLD) which is attached to the outer membrane of Escherichia coli (E. coli) has now been almost completely proven to be the basic cause of BPH. The evidence for this process is now extremely strong and compelling. PLD obtained from the organism Streptomyces chromofuscus has been used in past research because of its PLD content. It is commercially available. In vitro, on a culture of prostatic smooth muscle, PLD stimulated the production of lysophosphatidic acid (LPA) which acted on and caused substantial growth of that muscle in accordance with the quantity of PLD/ LPA generated. It has been asserted that repeated colonization by E. coli of the transitional zone of the prostate gland and the release of PLD following repeated destruction of these colonized bacteria, is the basic cause of BPH. The evidence for colonizing and re-colonizing infection is now overwhelming. PLD is a simple lipid consisting of a phosphate, glycerol and a fatty acid. After absorption into the prostatic stroma (which consists of connective tissue and of smooth muscle), it stimulates the production of LPA which, in turn, apart from directly stimulating prostatic smooth muscle, also acts on the connective tissue in the prostate and induces a complex mixture of growth regulatory proteins, which include members of the fibroblast, insulin-like and growth transforming factor families and implicates autocrine hormones acting on the stroma and paracrine hormones acting on epithelium. Also involved, are a variety of interleukins and other inflammatory cell cytokines, secreted by the stroma, which may further promote autocrine/paracrine proliferation of BPH cells

68Ga-PSMA PET/CT in prostate cancer.

PubMed

García Garzón, J R; de Arcocha Torres, M; Delgado-Bolton, R; Ceci, F; Alvarez Ruiz, S; Orcajo Rincón, J; Caresia Aróztegui, A P; García Velloso, M J; García Vicente, A M

Positron emission tomography/computed tomography (PET/CT) with 68 Ga-PSMA is a non-invasive diagnostic technique to image prostate cancer with increased prostate-specific membrane antigen (PSMA) expression. PSMA is a transmembrane protein present in all prostatic tissues. Increased PSMA expression is seen in several malignancies, although prostate cancer is the tumour where it presents higher concentrations. Almost all prostate adenocarcinomas show PSMA expression in most of lesions, primary and metastatic. Immunohistochemistry has demonstrated that the expression of PSMA increases in patients with de-differentiated, metastatic or hormone-refractory tumours. Moreover, the expression level of PSMA has a prognostic value for disease outcome. PET measures the three-dimensional distribution of 68 Ga-PSMA, producing semi-quantitative images that allow for non-invasive assessment of PSMA expression. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

Association between protein C levels and mortality in patients with advanced prostate, lung and pancreatic cancer.

PubMed

Wilts, I T; Hutten, B A; Meijers, J C M; Spek, C A; Büller, H R; Kamphuisen, P W

2017-06-01

Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer. The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models. We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07). Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Human osteocalcin and bone sialoprotein mediating osteomimicry of prostate cancer cells: role of cAMP-dependent protein kinase A signaling pathway.

PubMed

Huang, Wen-Chin; Xie, Zhihui; Konaka, Hiroyuki; Sodek, Jaro; Zhau, Haiyen E; Chung, Leland W K

2005-03-15

Osteocalcin and bone sialoprotein are the most abundant noncollagenous bone matrix proteins expressed by osteoblasts. Surprisingly, osteocalcin and bone sialoprotein are also expressed by malignant but not normal prostate epithelial cells. The purpose of this study is to investigate how osteocalcin and bone sialoprotein expression is regulated in prostate cancer cells. Our investigation revealed that (a) human osteocalcin and bone sialoprotein promoter activities in an androgen-independent prostate cancer cell line of LNCaP lineage, C4-2B, were markedly enhanced 7- to 12-fold in a concentration-dependent manner by conditioned medium collected from prostate cancer and bone stromal cells. (b) Deletion analysis of human osteocalcin and bone sialoprotein promoter regions identified cyclic AMP (cAMP)-responsive elements (CRE) as the critical determinants for conditioned medium-mediated osteocalcin and bone sialoprotein gene expression in prostate cancer cells. Consistent with these results, the protein kinase A (PKA) pathway activators forskolin and dibutyryl cAMP and the PKA pathway inhibitor H-89, respectively, increased or repressed human osteocalcin and bone sialoprotein promoter activities. (c) Electrophoretic mobility shift assay showed that conditioned medium-mediated stimulation of human osteocalcin and bone sialoprotein promoter activities occurs through increased interaction between CRE and CRE-binding protein. (d) Conditioned medium was found to induce human osteocalcin and bone sialoprotein promoter activities via increased CRE/CRE-binding protein interaction in a cell background-dependent manner, with marked stimulation in selected prostate cancer but not bone stromal cells. Collectively, these results suggest that osteocalcin and bone sialoprotein expression is coordinated and regulated through cAMP-dependent PKA signaling, which may define the molecular basis of the osteomimicry exhibited by prostate cancer cells.

Spirituality in men with advanced prostate cancer: "it's a holistic thing . . . it's a package".

PubMed

Lepherd, Laurence

2014-06-01

Spirituality is often regarded as being helpful during an unwell person's journey but definitions of the concept can be confusing, and its use synonymously with religion can be misleading. This research sought to answer the question, "What is the nature of spirituality in men with advanced prostate cancer," and to discover the role spirituality may have in these men as they face the challenges of living with their disease. A qualitative approach and narrative method was used to explore the spirituality of nine men with advanced prostate cancer who volunteered to participate and to tell the story of their cancer journey with particular focus on their spirituality. The study found that spirituality for these men, who were all Caucasians, was a "holistic thing" that involved physical, psychosocial, and spiritual matters that enabled them to transcend the everyday difficulties of their journey. Through their spirituality they obtained greater comfort and peace of mind during what was for many of them a very traumatic time. The central theme in the men's stories was that of connectedness-to themselves, to their partners, sometimes to a higher being, to other people such as their family and friends, and to other aspects of their lives.

Effect of propofol on androgen receptor activity in prostate cancer cells.

PubMed

Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

2017-08-15

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.

PubMed

Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

2014-04-01

Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bajusz, S.; Janaky, T.; Csernus, V.J.

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Ofmore » the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.« less

Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer.

PubMed

Murga, Jose D; Moorji, Sameer M; Han, Amy Q; Magargal, Wells W; DiPippo, Vincent A; Olson, William C

2015-02-15

Antibody-drug conjugates (ADCs) are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase 2 testing of an ADC targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer has shown antitumor activity. The present study examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds. Antiproliferative activity and expression of PSMA, prostate-specific antigen and androgen receptor were evaluated in the prostate cancer cell lines LNCaP and C4-2. Cells were tested for susceptibility to antiandrogens or other inhibitors, used alone and in combination with PSMA ADC. Potential drug synergy or antagonism was evaluated using the Bliss independence method. Enzalutamide and abiraterone demonstrated robust, statistically significant synergy when combined with PSMA ADC. Largely additive activity was observed between the antiandrogens and the individual components of the ADC (free drug and unmodified antibody). Rapamycin also synergized with PSMA ADC in certain settings. Synergy was linked in part to upregulation of PSMA expression. In androgen-dependent LNCaP cells, enzalutamide and abiraterone each inhibited proliferation, upregulated PSMA expression, and synergized with PSMA ADC. In androgen-independent C4-2 cells, enzalutamide and abiraterone showed no measurable antiproliferative activity on their own but increased PSMA expression and synergized with PSMA ADC nonetheless. PSMA expression increased progressively over 3 weeks with enzalutamide and returned to baseline levels 1 week after enzalutamide removal. The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer. © 2014 Wiley Periodicals, Inc.

Integrative clinical genomics of advanced prostate cancer.

PubMed

Robinson, Dan; Van Allen, Eliezer M; Wu, Yi-Mi; Schultz, Nikolaus; Lonigro, Robert J; Mosquera, Juan-Miguel; Montgomery, Bruce; Taplin, Mary-Ellen; Pritchard, Colin C; Attard, Gerhardt; Beltran, Himisha; Abida, Wassim; Bradley, Robert K; Vinson, Jake; Cao, Xuhong; Vats, Pankaj; Kunju, Lakshmi P; Hussain, Maha; Feng, Felix Y; Tomlins, Scott A; Cooney, Kathleen A; Smith, David C; Brennan, Christine; Siddiqui, Javed; Mehra, Rohit; Chen, Yu; Rathkopf, Dana E; Morris, Michael J; Solomon, Stephen B; Durack, Jeremy C; Reuter, Victor E; Gopalan, Anuradha; Gao, Jianjiong; Loda, Massimo; Lis, Rosina T; Bowden, Michaela; Balk, Stephen P; Gaviola, Glenn; Sougnez, Carrie; Gupta, Manaswi; Yu, Evan Y; Mostaghel, Elahe A; Cheng, Heather H; Mulcahy, Hyojeong; True, Lawrence D; Plymate, Stephen R; Dvinge, Heidi; Ferraldeschi, Roberta; Flohr, Penny; Miranda, Susana; Zafeiriou, Zafeiris; Tunariu, Nina; Mateo, Joaquin; Perez-Lopez, Raquel; Demichelis, Francesca; Robinson, Brian D; Schiffman, Marc; Nanus, David M; Tagawa, Scott T; Sigaras, Alexandros; Eng, Kenneth W; Elemento, Olivier; Sboner, Andrea; Heath, Elisabeth I; Scher, Howard I; Pienta, Kenneth J; Kantoff, Philip; de Bono, Johann S; Rubin, Mark A; Nelson, Peter S; Garraway, Levi A; Sawyers, Charles L; Chinnaiyan, Arul M

2015-05-21

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

Integrative clinical genomics of advanced prostate cancer

PubMed Central

Dan, Robinson; Van Allen, Eliezer M.; Wu, Yi-Mi; Schultz, Nikolaus; Lonigro, Robert J.; Mosquera, Juan-Miguel; Montgomery, Bruce; Taplin, Mary-Ellen; Pritchard, Colin C; Attard, Gerhardt; Beltran, Himisha; Abida, Wassim M.; Bradley, Robert K.; Vinson, Jake; Cao, Xuhong; Vats, Pankaj; Kunju, Lakshmi P.; Hussain, Maha; Feng, Felix Y.; Tomlins, Scott A.; Cooney, Kathleen A.; Smith, David C.; Brennan, Christine; Siddiqui, Javed; Mehra, Rohit; Chen, Yu; Rathkopf, Dana E.; Morris, Michael J.; Solomon, Stephen B.; Durack, Jeremy C.; Reuter, Victor E.; Gopalan, Anuradha; Gao, Jianjiong; Loda, Massimo; Lis, Rosina T.; Bowden, Michaela; Balk, Stephen P.; Gaviola, Glenn; Sougnez, Carrie; Gupta, Manaswi; Yu, Evan Y.; Mostaghel, Elahe A.; Cheng, Heather H.; Mulcahy, Hyojeong; True, Lawrence D.; Plymate, Stephen R.; Dvinge, Heidi; Ferraldeschi, Roberta; Flohr, Penny; Miranda, Susana; Zafeiriou, Zafeiris; Tunariu, Nina; Mateo, Joaquin; Lopez, Raquel Perez; Demichelis, Francesca; Robinson, Brian D.; Schiffman, Marc A.; Nanus, David M.; Tagawa, Scott T.; Sigaras, Alexandros; Eng, Kenneth W.; Elemento, Olivier; Sboner, Andrea; Heath, Elisabeth I.; Scher, Howard I.; Pienta, Kenneth J.; Kantoff, Philip; de Bono, Johann S.; Rubin, Mark A.; Nelson, Peter S.; Garraway, Levi A.; Sawyers, Charles L.; Chinnaiyan, Arul M.

2015-01-01

SUMMARY Toward development of a precision medicine framework for metastatic, castration resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin and ZBTB16/PLZF. Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides evidence that clinical sequencing in mCRPC is feasible and could impact treatment decisions in significant numbers of affected individuals. PMID:26000489

Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.

PubMed

Jongsma, Johan; Oomen, Monique H; Noordzij, Marinus A; Van Weerden, Wytske M; Martens, Gerard J M; van der Kwast, Theodorus H; Schröder, Fritz H; van Steenbrugge, Gert J

2002-03-01

Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310. Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation. Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively. Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells

The Hsp90 Inhibitor, 17-AAG, Prevents the Ligand-Independent Nuclear Localization of Androgen Receptor in Refractory Prostate Cancer Cells

PubMed Central

Saporita, Anthony J.; Ai, Junkui; Wang, Zhou

2010-01-01

BACKGROUND Androgen receptor (AR) is the key molecule in androgen-refractory prostate cancer. Despite androgen ablative conditions, AR remains active and is necessary for the growth of androgen-refractory prostate cancer cells. Nuclear localization of AR is a prerequisite for its transcriptional activation. We examined AR localization in androgen-dependent and androgen-refractory prostate cancer cells. METHODS AND RESULTS We demonstrate increased nuclear localization of a GFP-tagged AR in the absence of hormone in androgen-refractory C4-2 cells compared to parental androgen-sensitive human prostate cancer LNCaP cells. Analysis of AR mutants impaired in ligand-binding indicates that the nuclear localization of AR in C4-2 cells is truly androgen-independent. The hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), inhibits basal PSA expression and disrupts the ligand-independent nuclear localization of AR at doses much lower than required to inhibit androgen-induced nuclear import. CONCLUSIONS Hsp90 is a key regulator of ligand-independent nuclear localization and activation of AR in androgen-refractory prostate cancer cells. PMID:17221841

Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

PubMed

Bonkhoff, Helmut

2018-01-01

The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling.

PubMed

Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook; Baek, Songjoon; Sung, Myong-Hee; Zhao, Li; Park, Jeong Won; Nielsen, Ronni; Walker, Robert L; Zhu, Yuelin J; Meltzer, Paul S; Hager, Gordon L; Cheng, Sheue-yann

2015-04-28

A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription. Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand.

Experiences of Australian men diagnosed with advanced prostate cancer: a qualitative study