Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Survival Rate and Factors Influencing It in Triptorelin-Castrated Metastatic Prostate Cancer Patients

Background: Most newly diagnosed prostate cancers in Benin are metastatic diseases and patients are reluctant to undergo orchiectomy. Still, chemical androgen deprivation therapy is not always available and not every patient can afford it. Thus, it will be interesting to evaluate the results of that therapy in the country. Objective: To analyze the survival rate and factors influencing it in metastatic prostate cancer patients who underwent triptorelin-based androgen deprivation therapy at the former Military Teaching Hospital of Cotonou from January 1, 2012, to December 31, 2022. Patients and Method: Metastatic prostate cancer patients received intragluteal injections of triptorelin 11.25 mg every 3 months. We retrospectively collected follow-up data from the patients’ medical records. By means of the software StataTM version 15, we performed a descriptive analysis of qualitative data. We used Kaplan-Meir method to estimate the overall survival rate in the whole cohort and in specific subgroups of patients. We compared survival rates by using the log-rank test. Results: 68 metastatic prostate cancer patients aged 47-86 years (mean = 69.9) with initial PSA ranging from 24.25 to 6334 ng/mL (mean = 666.1) started triptorelin-based castration. The tumor grade in 21 (33.3%), 14 (22.2%), 15 (23.8), 8 (12.7%), and 5 (7.9%) patients was respectively ISUP grade groups 5, 4, 3, 2, and 1. 15 (22.1%), 4 (5.9%), 2 (2.9%), 1 (1.5%), 11 (16.2%), and 7 (10.3%) patients respectively had hypertension, diabetes mellitus, peptic ulcer, asthma, unilateral or bilateral hydronephrosis, and paralysis. The mean nadir PSA level was 22.5 ng/mL (range: 0.01-220.25). The mean time to nadir PSA level was 8.9 months (range: 3-57). The overall survival rate was 42.6%. There was no significant survival difference between age groups (p = 0.475), relating to the presence of diabetes or hypertension (p = 0.757) or to the presence of paralysis or hydronephrosis (p = 0.090). The initial PSA level exerted no significant impact on patients’ survival (p = 0.461). Neither did the time to PSA nadir (p = 0.263). The PSA nadir less than 4 ng/mL (p = 0.005) and the PSA nadir less than 4 ng/mL achieved in 12 months or less (p = 0.002) were predictive of longer survival rate. The difference in survival rate through the ISUP grade groups was not significant (p = 0.061). Conclusion: The overall survival rate was 42.6% at 5 years. Achieving PSA nadir of less than 4 ng/mL in less than 12 months of castration was predictive of longer survival rate in triptorelin-castrated metastatic prostate cancer patients.

PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

Androgen receptor signaling and mutations in prostate cancer

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.

Efficacy of maximal androgen blockade versus castration alone in the treatment of advanced prostate cancer： a retrospective clinical experience from a Chinese medical centre

In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.

Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

Prostate cancer （PCa） is the most common visceral malignancy in men with androgen deprivation therapy （ADT） the preferred therapy to suppress testosterone production and hence tumor growth. Despite its effectiveness in lowering testosterone, ADT is associated with side effects including loss of muscle mass, diminished muscle strength, decrements in physical performance, earlier fatigue and declining quality of life. This review reports a survey of the literature with a focus on changes in muscle strength, physical function and body composition, due to short-term and long-term ADT. Studies in these areas are sparse, especially well-controlled, prospective randomized trials. Cross-sectional and longitudinal data （up to 2 years） for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available. Based on limited longitudinal data, the adverse effects of ADT on muscle function, physical performance and body composition occur shortly after the onset of ADT and tend to persist and worsen over time. Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine. Disparities in study duration, types of studies and other patient-specific variables such as time since diagnosis, cancer stage and comorbidities may all affect an understanding of the influence of ADT on health, physical performance and mortality.

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

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.

Effect of androgen deprivation therapy on bone mineral density in prostate cancer patients

Aim: To evaluate the effect of androgen deprivation therapy (ADT) on bone mineral density (BMD) in prostate cancer patients. Methods: Forty-nine prostate cancer patients with their BMD determined were divided into two groups: the non-treated group included 21 patients before the commencement of ADT and the treated group, 28 patients, who had received ADT for more than 1 year. BMD was measured by dual energy X-ray absorptiometry (DEXA) in the lumbar spine (L2-4) and femoral neck. Results: Thirteen (62 %) non-treated and 23 (82 %) treated patients fulfilled the BMD criteria for osteopenia or osteoporosis. Z scores for age-matched control in lumbar spine and femoral neck were -0.9 ± 0.7 and -0.6 ± 0.5, respectively, in the treated group, and -1.8 ± 1.1 and-1.6 ± 1.0 , respectively, in the non-treated group, the differences between the two groups were highly significant (P<0.01). Conclusion: Prostate cancer patients who received ADT for more than 1 year had a significantly lower BMD in the lumbar spine and femoral neck than those before the beginning of ADT.

The androgen receptor in hormone-refractory prostate cancer

Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor （AR） signalling. However, the effect is short-lived, as nearly all tumours progress to a hormone-refractory （HR） state, a lethal stage of the disease. Intuitively, the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR tumours. However, there is still a consensus that AR plays an essential role in HR prostate cancer （HRPC） because AR signalling is still functional in HR tumours. AR signalling can be activated in HR tumours through several mechanisms. First, activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens. Also, mutations in the AR can change AR ligand specificity, thereby allowing it to be activated by non-steroids or anti-androgens. Finally, overexpression of the wild-type AR sensitizes itself to low concentrations of androgens. Therefore, drugs targeting AR signalling could still be effective in treating HRPC.

Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro

For more than 70 years, it has been believed that a severe reduction of serum androgen levels caused regression of prostate cancer （PCa） and that increasing androgen levels enhanced growth of PCa. However, numerous recent studies have questioned this traditional belief. In our study, LNCaP and MDA PCa 2b PCa cells were treated with various levels of androgens for 10 or 20 days, and the cell growth was measured with crystal violet mitogenic assay. The results indicated that the effect of androgens on the proliferation of PCa cells occurs in a biphasic pattern, with the androgen levels promoting optimal cell growth at approximately 0.23 ng m1-1 for LNCaP cells and between I and 2 ng m1-1 for MDA PCa 2b cells. Both of the optimal androgen levels are within the adult men＇s physiological low range （〈2.4 ng ml-1）. At lower concentrations than the optimal androgen level, increasing androgen concentration promoted the proliferation of PCa cells. However, at the higher concentrations, increasing androgen concentration resulted in a dose-dependent proliferative inhibition. We conclude that physiologically normal levels of androgen inhibit the proliferation of PCa cells in vitro. However, at very low levels androgens are essential for initial growth of PCa cells.

Androgen receptor expression in clinically localized prostate cancer： immunohistochemistry study and literature review

Aim： To evaluate androgen receptor （AR） expression in clinically localized prostate cancer （PCa）. Methods： Specimens were studied from 232 patients who underwent radical prostatectomy for clinically localized prostatic adenocarcinoma without neoadjuvant hormonal therapy or chemotherapy at our institution between November 2001 and June 2005. Immunohistochemical study was performed using an anti-human AR monoclonal antibody AR441. The mean AR density in the hot spots of different histological areas within the same sections were compared and the correlation of malignant epithelial AR density with clinicopathological parameters such as Gleason score, tumor, nodes and metastases （TNM） stage and pre-treatment prostate-specific antigen （PSA） value was assessed. Results： AR immunoreactivity was almost exclusively nuclear and was observed in tumor cells, non-neoplastic glandular epithelial cells and a proportion of peritumoral and interglandular stromal cells. Mean percentage of AR-positive epithelial cells was significantly higher in cancer tissues than that in normal prostate tissues （mean e SD, 90.0% ± 9.3% vs. 85.3% ±9.7%, P 〈 0.001）. The histological score yielded similar results. The percentage ofAR immunoreactive prostatic cancer nuclei and histological score were not correlated with existing parameters such as Gleason score, tumor, nodes and metastases stage and pre-treatment PSA value in this surgically treated cohort. Conclusion： The results of the present study suggest that there may be limited clinical use for determining AR expression （if evaluated in hot spots） in men with localized PCa.

Anemia in patients on combined androgen block therapy for prostate cancer

Aim: To study the effect of combined androgen block therapy on hemoglobin and hematocrit values in patients with prostate cancer. Methods: One hundred and thirty-six patients with adenocarcinoma of prostate were treated with combined androgen block (orchiectomy and flutamide 250 mg, tid). Complete blood counts were determined before and after 1, 2, 3, 6, 9 and 12 months of therapy. Results: The hemoglobin and hematocrit levels declined significantly in all patients and at all the time points after treatment (P<0.05). Conclusion: Prostate cancer patients treated with combined androgen block would develop obvious anemia. Recombinant human erythropoietin can be used to treat patients with severe anemia.

Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells

Aim： To characterize the matrix metalloproteinases （MMP）-2 promoter and to identify androgen response elements （AREs） involved in androgen-induced MMP-2 expression. Methods： MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction （RT-PCR）. MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays （EMSA） were used to verify the identified AREs in the MMP-2 promoter. Results： Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1591 to -1259 （relative to the start codon） of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5＇-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor （AR） interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment. Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. Conclusion： Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（^-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （OS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.

Effects of Exercise on Cancer-related Fatigue and Quality of Life in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Meta-analysis of Randomized Clinical Trials

Objective To gain insight on how exercise affects the outcomes of prostate cancer patients treated with androgen deprivation therapy,specifically cancer-related fatigue(CRF) and quality of life(QoL). Methods Systematic searches for randomized clinical trials(RCTs) evaluating the effects of exercise on CRF and QoL of prostate cancer patients receiving androgen deprivation therapy were carried out to identify the eligible studies from EMBASE,Pub Med and Cochrane library. Related data were extracted from eligible studies and then subjected to Reviewer Manage 5.3 for analysis. Standardized mean differences(SMD) and its 95% confidence interval(CI) were calculated. Results In all,10 RCTs involving 841 prostate cancer patients(448 of whom exercised and 393 did not) were included in this study. With respect to CRF,there was good consistency among different studies,and it was remarkably reduced in the exercise group(SMD=-0.32,95% CI:-0.45 to-0.18,P<0.00001,n=784). In regards to QoL,there was also good consistency among different studies,and it was also improved significantly in the exercise group(SMD=0.21,95% CI:0.08 to 0.34,P=0.002,n=841). Conclusion Exercise both reduced CRF and improved QoL in prostate cancer patients receiving androgen deprivation therapy.

Posttranslational regulation of androgen dependent and independent androgen receptor activities in prostate cancer

Prostate cancer(PCa)is the most commonly diagnosed cancer among men in western countries.Androgen receptor(AR)signaling plays key roles in the development of PCa.Androgen deprivation therapy(ADT)remains the standard therapy for advanced PCa.In addition to its ligand androgen,accumulating evidence indicates that posttranscriptional modification is another important mechanism to regulate AR activities during the progression of PCa,especially in castration resistant prostate cancer(CRPC).To date,a number of posttranscriptional modifications of AR have been identified,including phosphorylation(e.g.by CDK1),acetylation(e.g.by p300 and recognized by BRD4),methylation(e.g.by EZH2),ubiquitination(e.g.by SPOP),and SUMOylation(e.g.by PIAS1).These modifications are essential for the maintenance of protein stability,nuclear localization and transcriptional activity of AR.This review summarizes posttranslational modifications that influence androgen-dependent and-independent activities of AR,PCa progression and therapy resistance.We further emphasize that in addition to androgen,posttranslational modification is another important way to regulate AR activity,suggesting that targeting AR posttranslational modifications,such as proteolysis targeting chimeras(PROTACs)of AR,represents a potential and promising alternate for effective treatment of CRPC.Potential areas to be investigated in the future in the field of AR posttranslational modifications are also discussed.

Androgen receptors expressed by prostatic stromal cells obtained from younger versus older males exhibit opposite roles in prostate cancer progression

Aging is a major risk factor for prostate cancer （PCa）, and prostatic stromal cells may also promote PCa progression. Accordingly, stromal cells do not equally promote PCa in older males and younger males. Therefore, it is also possible that the expression of androgen receptors （ARs） by prostatic stromal cells in older versus younger males plays different roles in PCa progression. Using a gene knockdown technique and coculture system, we found that the knockdown of the AR in prostatic stromal cells obtained from younger males could promote the invasiveness and metastasis of cocultured PC3/LNCaP cells in vitro. By contrast, the invasiveness and metastasis of LNCaP cells was inhibited when cocultured with prostatic stromal cells from older males that when AR expression was knocked down. Moreover, after targeting AR expression with small hairpin RNA （shRNA）, matrix metalloproteinase （MMP） expression in stromal cells was observed to increase in the younger group, but decreased or remained unchanged in the older group. One exception, however, was observed with MMP9. In vivo, after knocking down AR expression in prostatic stromal cells, the incidence of metastatic lymph nodes was observed to increase in the younger age group, but decreased in the older age group. Together, these data suggest that the AR in prostatic stromal cells played opposite roles in PCa metastasis for older versus younger males. Therefore, collectively, the function of the AR in prostatic stromal cells appears to change with age, and this may account for the increased incidence of PCa in older males.

Deoxynortryptoquivaline:A unique antiprostate cancer agent

The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new ARinhibitor, we constructed a new screening system using the androgen-dependent growth of prostate cancer cell lines as ascreening indicator. We screened 50,000 culture broths of microorganisms using this screening system and found that thefermentation broth produced by a fungus inhibited androgen-dependent growth of human prostate cancer LNCaP cellswithout cytotoxicity. Purification of this culture medium was performed, and this resulted in deoxynortryptoquivaline(DNT) being identified as a novel inhibitor of AR function. DNT showed potent inhibition of androgen-dependentgrowth of human prostate cancer LNCaP cells. The AR competitor assay was performed, and DNT did not act as anAR antagonist. However, DNT inhibited AR-dependent transcriptional activity and AR nuclear translocation, itsuggested that the suppression of AR function leads to inhibition activity against androgen-dependent growth.

Identification of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer

Race, family history and age are the unequivocally accepted risk factors for prostate cancer （PCa）. Androgen receptor （AR）-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR （A1675T） （T559S） substitution mutation in the DNA-binding domain in three PCa-affected members of an African- American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR （T559S） mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR （A 1675T） allele to early-onset and/or familial PCa in African Americans.

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.