Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

Management of locally advanced prostate cancer

The management of all stages of prostate cancer is an increasingly complex process and involves a variety of available treatments and many disciplines. Despite prostate-specific antigen （PSA） testing, the presentation of prostate cancer at a locally advanced stage is common in the UK, accounting for one-third of all new cases. There is no universally accepted definition of locally advanced prostate cancer; the term is loosely used to encompass a spectrum of disease profiles that show high-risk features. Men with high-risk prostate cancer generally have a significant risk of disease progression and cancer-related death if left untreated. High-risk patients, including those with locally advanced disease, present two specific challenges. There is a need for local control as well as a need to treat any microscopic metastases likely to be present but undetectable until disease progression. The optimal treatment approach will therefore often necessitate multiple modalities. The exact combinations, timing and intensity of treatment continue to be strongly debated. Management decisions should be made after all treatments have been discussed by a multidisciplinary team （including urologists, oncologists, radiologists, pathologists and nurse specialists） and after the balance of benefits and side effects of each therapy modality has been considered by the patient with regard to his own individual circumstances. This article reviews the current therapy options.

Contraceptive effect of Curcuma longa (L.) in male albino rat

Aim: To study the contraceptive effect of the crude extracts of Curcuma longa in male albino rats. Methods: Rats were fed orally with Curcuma longa aqueous and 70 % alcoholic extract for 60 days (500 mg·kg-1· day-1). Results: A reduction in sperm motility and density was observed in both the treated groups. Conclusion: Curcuma longa may have affected the androgen synthesis either by inhibiting the Leydig cell function or the hypo-thalamus pituitary axis and as a result, spermatogenesis is arrested.

In vivo modulation of androgen receptor by androgens

Aim: To study the effect of androgen and antiandrogen on the level of androgen receptor (AR) mRNA. Methods: The total RNA was extracted from the prostate and analyzed by slot blot analysis. The blots were hybridized with AR cDNA probe and 1A probe (internal control) and autoradiography was performed. The intensity of signal was measured with a densitometer and the ratio of AR RNA and 1A RNA was calculated. Results: Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of AR mRNA. Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of AR mRNA. Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels Of AR mRNA. Conclusion: Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.

Long-term effectiveness of luteinizing hormone-releasing hormone agonist or antiandrogen monotherapy in elderly men with localizect prostate cancer （T1-2） ： a retrospective study

Aim： To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs （luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen） that were used individually to treat patients with localized prostate cancer （T1-2） at our institution. Methods： Ninety-seven patients who were diagnosed in the period from April 1997 to January 2000 as having clinically localized prostate cancer （T1-2） received either LHRH agonist （leuprolide acetate 7.5 mg/month） monotherapy （group 1, n = 62） or antiandrogen monotherapy （group 2, n = 35; 18 received bicalutamide 50 mg q.d., 13 received nilutamide 150 mg t.i.d, and 4 received flutamide 250 mg t.i.d.）. The mean age in both groups was 76 years. Results： The mean follow-up time was （50.8 ±8.5） months in group 1 and （43.1 ± 2.2） months in group 2. Prostate-specific antigen （PSA） levels rose in only 1 of the 62 patients （1.6%） in group 1, and in 20 of the 35 patients （57.1%） in group 2. In group 2, 10 of the 20 patients （50 %） with increasing PSA levels were treated with LHRH salvage therapy, and eight （80%） responded. Hot flashes （54.8%） and lethargy （41.9%） were the most common side effects in group 1. In contrast, nipple-tenderness （40%） and light-dark adaptation （17.1%） were more often seen in group 2. Only 1 of the 62 patients （1.6%） in group 1 switched to another medication because of adverse side effects; whereas 8 of the 35 patients （22.9%） in group 2 did so. Conclusion： Unlike antiandrogen monotherapy, LHRH agonist monotherapy provided long-term durable control of localized prostate cancer （T1-2）. It can also be an effective treatment option for patients whose disease failed to respond to antiandrogen monotherapy. The limitations of our study are the lack of health outcomes analysis and a small sample size.

Antispermatogenic and hormonal effects of Crotalaria junceaLinn. seed extracts in male mice

Aim: To evaluate the antifertility activity of various extracts of Crotalaria juncea seeds in male mice. Methods: Adult male mice were gavaged the petroleum ether, benzene and ethanol extracts of C. juncea seeds, 25 mg·(100g)-1·day-1 for 30 days. On day 31 the animals were sacrificed by cervical dislocation and the testes, epididymis, vas deferens, seminal vesicles, prostate gland, bulbourethral gland and levator ani were dissected out and weighed. The organs were processed for biochemical and histological examination. Results: In petroleum ether, benzene and ethanol extracts treated rats, there was a decrease in the weights of testis and accessory reproductive organs. The diameters of the testis and seminiferous tubules were decreased. Spermatogonia, spermatocytes and spermatids in the testis and the sperm count in cauda epididymis were also decreased. There was a significant reduction in the protein and glycogen contents and an increase in the cholesterol content in the testis, epididymis and vas deferens. Of the 3 extracts, the ethanol extract appeared to be the most potent in antispermatogenic activity. When the ethanol extract was tested in immature male mice, there was an antiandrogenic effect as the weights of accessory organs were reduced. Conclusion: The various extracts of C. juncea seeds arrest spermatogenesis and are likely to have an antiandrogenic activity.

Novel flutamide regulated genes in the rat veritral prostate： differential modulation of their expression by castration and flutamide treatments

Aim： To identify flutamide regulated genes in the rat ventral prostate. Methods： Total RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamideregulated transcripts was studied. Results： We have identified β2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin Ⅱ as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 rnRNA, castration had no effect. Conclusion： Castration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

The Antiandrogen Withdrawal Syndrome

Objective\ To evaluate the response to antiandrogen withdrawal in patients with advanced prostate cancer treated with combined androgen blockade. Methods\ Twenty four cases of advanced prostate cancer (10 in stage C and 14 in stage D) were retrospectively studied. All the patients were treated with combined androgen blockade (bilateral orchiectomy and flutamide). After initial response to hormone therapy for 7 to 36 months, flutamide was discontinued because of deterioration of the disease. Serum prostate specific antigen (PSA) levels were checked every 2 to 4 weeks and symptoms observed. Results\ The results following withdrawal of flutamide were as follows: 8 patients showed a decline in PSA (mean 74.8%), of whom 6 cases had the PSA decline greater than 50%. Clinical symptoms improved in 4 cases. The nodules of the prostate were smaller than before in cases. The mean duration of response was 4.3 months.Conclusion\ In patients with hormone refractory advanced prostate cancer after initial combined androgen blockade therapy, a trial of 'antiandrogen withdrawal' is a reasonable choice of therapeutic maneuver.

Role of prostate cancer stem-like cells in the development of antiandrogen resistance

Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

Biological removal of antiandrogenic activity in gray wastewater and coking wastewater by membrane reactor process

A recombinant human androgen receptor yeast assay was applied to investigate the occurrence of antiandrogens as well as the mechanism for their removal during gray wastewater and coking wastewater treatment. The membrane reactor（MBR） system for gray wastewater treatment could remove 88.0% of antiandrogenic activity exerted by weakly polar extracts and 97.3% of that by moderately strong polar extracts, but only 32.5%of that contributed by strong polar extracts. Biodegradation by microorganisms in the MBR contributed to 95.9% of the total removal. After the treatment, the concentration of antiandrogenic activity in the effluent was still 1.05 μg flutamide equivalence（FEQ）/L, 36.2%of which was due to strong polar extracts. In the anaerobic reactor, anoxic reactor, and membrane reactor system for coking wastewater treatment, the antiandrogenic activity of raw coking wastewater was 78.6 mg FEQ/L, and the effluent of the treatment system had only 0.34 mg FEQ/L. The antiandrogenic activity mainly existed in the medium strong polar and strong polar extracts. Biodegradation by microorganisms contributed to at least 89.2%of the total antiandrogenic activity removal in the system. Biodegradation was the main removal mechanism of antiandrogenic activity in both the wastewater treatment systems.

Prior switching to a second-line nonsteroidal antiandrogen does not impact the therapeutic efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer： a real-world retrospective study

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen （NSAA） is still widely used in treating metastatic castration-resistant prostate cancer （mCRPC）, especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate （Abi） remains uncertain, in the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA （from bicalutamide to flutamide） before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival （PSA-PFS, 5.5 vs 5.6 months, P = 0.967）, radiographic progression-free survival （rPFS, 12.8 vs 13.4 months, P = 0.508）, overall survival （OS, not reached vs 30.6 months, P = 0.606）, or PSA-response rate （71.4% [15121] vs 60.6% [40166], P = 0.370）. This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors＇ decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.

Treatment strategy for metastatic prostate cancer with extremely high PSA level： reconsidering the value of vintage therapy

The prognostic significance of initial prostate-specific antigen （PSA） level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows： low （〈100 ng ml-1）, intermediate （100–999 ng ml-1）, and high （≥1000 ng ml-1）. All patients received androgen deprivation therapy （ADT） immediately. We investigated PSA progression-free survival （PFS） for first-line ADT and overall survival （OS） within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal （AW） and alternative antiandrogen （AA） therapies after development of castration-resistant prostate cancer （CRPC）. No significant differences in OS were observed among the three groups （P = 0.654）. Patients with high PSA levels had significantly short PFS for first-line ADT （P = 0.037）. Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group （P = 0.047）. Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy （P = 0.049）. PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders （P = 0.011 and P 〈 0.001, respectively）. Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.