Castration Therapy Research Articles

Circulating estrogen receptor (ER) mutations and splice variants in men with advanced prostate cancer (APC).

363 Background: Circulating DNA and RNA have been studied in APC as biomarkers of potential clinical significance. Candidates include androgen receptor amplification or emergence of splice variants. ER signalling has been associated with prostate cancer progression in vitro but blood-based detection of ER variants has not been studied. Methods: Men with APC were recruited for serial blood collection during routine management, from which cell-free DNA (cfDNA) and cell-free RNA (cfRNA) were extracted. Six well-described ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N & D538G) and six ER splice variants (ERα-66, ERα-36, ERβ1, ERβ2, ERβ4 & ERβ5) were quantitated using droplet digital polymerase chain reaction. These markers were explored in association with clinical and treatment variables using descriptive statistics. Results: 44 men were included for a total of 92 cfDNA and 94 cfRNA samples, with a median of 2 (range: 1-6) sequential samples per patient. Two mutations (E380Q & D538G) were detected in both cfDNA and cfRNA samples, and two (L536Q & Y537S) were detected in cfRNA samples only. The ER splice variants were widely detected in cfRNA samples, including in non-cancer controls. ERα-36 was detected at lower levels than the other splice variants investigated (p < 0.0001). Despite ubiquitous detection, the levels of splice variants altered consistently with analysis of the following clinical variables: during castration therapy; following castration resistance; and with number of previous treatments. No clear patterns of expression were observed for ER mutants. Serial sample analysis associated increased ERα-36 levels with response to docetaxel or abiraterone therapy. ERβ splice variant levels decreased with progression on all studied therapies. Development of E380Q and L536Q mutations was observed in patients with disease progression. Conclusions: We identified circulating ER mutants and splice variants in men with APC. These variants may be associated with previous treatment use, as well as disease progression on castration therapy or other APC treatments. Further work will explore their utility for predicting treatment response.

Protocols for the Study of Taxanes Chemosensitivity in Prostate Cancer.

Prostate cancer is major cause of cancer-related death among men in Western countries. Locally advanced prostate cancers are treated with castration therapy, which is initially effective, but after months the disease progresses to a hormone-refractory state whose treatment is chemotherapy based on taxanes. Although taxanes improve the survival of patients with castration-resistant prostate cancers, these patients often develop chemotherapy resistance, and new therapeutic strategies are necessary. Taxanes exert their action through interaction with β-tubulin which triggers cell cycle arrest in mitosis and the subsequent induction of the intrinsic apoptotic pathway. Since taxanes are widely used for the treatment of advanced prostate cancers, we present in this chapter protocols that allow the study of the prostate cancer sensitivity as well as determine the mechanisms of resistance to these chemotherapeutic agents.

HMGB1-mediated autophagy confers resistance to gemcitabine in hormone-independent prostate cancer cells.

As a main treatment of prostate cancer, castration therapy has been widely applied in the clinic. However, the therapeutic strategy for hormone-independent prostate cancer (HIPC) was not satisfied. Gemcitabine is an important chemotherapeutic agent that has been approved for the treatment of numerous human solid tumors, including HIPC, whereas the gemcitabine resistance has become a serious problem in clinical chemotherapy. In the present study, the mechanisms of resistance to gemcitabine were investigated in HIPC cell lines. The results demonstrated that the autophagy markers were induced significantly in HIPC cells subsequent to gemcitabine treatment. Meanwhile, administration of gemcitabine to HIPC cells increased the expression of high mobility group box1 (HMGB1). Furthermore, the gemcitabine-induced autophagy response was attenuated in stable HIPC cells harboring HMGB1 shRNA. Notably, the HIPC cells stably transfected with HMGB1 shRNA or treated with autophagy inhibitors were more sensitive to gemcitabine compared with the control group. These data suggested that inhibition of HMGB1 increased the sensitivity to gemcitabine by decreasing autophagy response in HIPC cells. Overall, the present findings demonstrate a new mechanism for the resistance to gemcitabine in HIPC cell lines.

Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe

BackgroundEnzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. ObjectiveTo fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Design, setting, and participantsMulticentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. InterventionPatients received enzalutamide 160mg/d orally. Outcome measurements and statistical analysisThe primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Results and limitationsOverall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1–8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6–5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. ConclusionsEnzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patient summaryPatients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment.

Androgen receptor variants in prostate cancer

Prostate cancer is a public health concern as it currently represents the most frequent malignancy in men in Europe. Progression of this hormone-dependent cancer is driven by androgens. Thus, the most common treatment for patients with advanced prostate cancer consists in an androgen ablation by castration therapy. However, the majority of patients relapses and develops a castration-resistant prostate cancer. This failure of androgen deprivation is related to the emergence of mutant and splice variants of the androgen receptor. Indeed, androgen receptor variants are ligand-independent, constitutively active and thus able to induce resistance to castration. This review focuses on AR variants signaling pathways and their role in resistance to castration and prostate cancer progression.

Abstract LB-030: Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression

Abstract Prostatic adenocarcinoma (PCa) remains the most frequently diagnosed cancer type and the third leading cause of cancer death in men in the United States. While organ-confined disease is manageable, treatment options for disseminated PCa remain limited. First-line therapy for metastatic PCa functions through targeting the androgen receptor (AR) signaling axis, as AR activity is required for tumor maintenance. However, while treatment is initially effective, these tumors invariably recur, displaying reactivation of AR signaling despite continued therapeutic targeting. Moreover, no durable treatment currently exists for this ultimately fatal disease stage, termed castrate-resistant PCa (CRPC). Significantly, recent high profile, genome-wide studies have revealed that missense mutations in the TP53 gene occur in nearly all cancer types, and these mutations frequently occur at specific TP53 “hotspots”. Interestingly, enrichment of certain hotspot p53 mutants specifically occurs in PCa. While the underlying causes of PCa-enriched mutations remain undefined, their presence elicits contrasting, pro-oncogenic biochemical and biological phenotypes. Unpublished data suggests that mutant p53 isoforms act in a mutation-specific fashion to drive PCa progression through alterations in the canonical activity of p53, identified through characterization of their related transcriptomes and cistromes. Biologically, these mutant p53 isoforms also confer differential proliferative and survival phenotypes. Moreover they act in a mutation-dependent fashion in response to castration therapy both in vitro and in vivo. Mechanistically, pro-oncogenic mutant p53 appears to manipulate both conventional and novel pathways leading to PCa progression. These findings both corroborate and expand the recent findings that mutations in p53 drive cancer progression, and further suggest a critical role for p53 mutations as regulators of disease progression in PCa. Citation Format: Jennifer J. McCann, Jeffry L. Dean, Renee De Leeuw, Matthew J. Schiewer, Christopher M. McNair, Karen E. Knudsen. Specific missense mutations in TP53 elicit contrasting biochemical and biological outcomes affecting prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-030. doi:10.1158/1538-7445.AM2017-LB-030

Abstract 1514: A novel approach for targeting androgen receptor signaling axis in prostate cancer

Abstract Background and Objectives: The androgen receptor (AR) is a ligand-activated transcription factor (TF) that plays critical oncogenic roles. Medical castration therapy is the mainstay treatment for advanced PrCa, but the AR signaling axis frequently remains active in castration-resistant PrCa (CRPC). Despite advances in AR targeting with abiraterone and enzalutamide, disease progression re-occurs in the form of CRPCs that still express AR-dependent genes. This highlights the need for novel approaches to block AR signaling and CRPC growth. The GATA family of TFs contains six members in mammals, all of which bind a consensus DNA sequence (A/T)GATA(A/G) to regulate gene expression. GATA2 is the predominant family member in prostate luminal epithelial cells. In a search for TFs that control AR expression, we found that GATA2 induces AR gene expression as well as promotes the recruitment of coactivators to the AR transcriptional complex. We found that GATA2 protein expression was strongly correlated with AR protein expression (Spearman's correlation coefficient: 0.323, p-value <0.0001) in our PrCa specimens (n=383). The intensity of GATA2 immunostaining in our BCM patient cohort positively correlated with Gleason score (R=0.37, p-value <0.01) and was a significant predictor of biochemical recurrence (p-value <0.001). We also demonstrated that GATA2 directly promotes expression of both full-length and AR splice-variant, resulting in a strong positive correlation between GATA2 and AR expression in both PrCa cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and AR splice-variants. Using ChIP-Seq we found that GATA2 colocalizes with AR and Forkhead box protein A1 (FOXA1) on chromatin to enhance recruitment of steroid receptor coactivators (SRC1, SRC2, and SRC3) and formation of the transcriptional holocomplex. Lastly, we identified a GATA2 small molecule inhibitor (SMI) that can suppress the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PrCa cell lines. We propose that the inhibition of GATA2 is a ‘first-in-field’ approach to target AR expression and function, including ligand-independent AR, for the treatment of CRPC. Citation Format: Salma Kaochar, Christopher Foley, Cristian Coarfa, Nicholas Mitsiades. A novel approach for targeting androgen receptor signaling axis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1514. doi:10.1158/1538-7445.AM2017-1514

Efficacy and safety of enzalutamide (ENZA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (Abi): A multicenter, single-arm, open-label study.

165 Background: This phase 4, multicenter, single-arm, open-label study evaluated the efficacy and safety of ENZA in patients (pts) with progressing mCRPC previously treated with Abi. Methods: All pts maintained castration therapy with luteinizing hormone-releasing hormone for the duration of the trial or had a bilateral orchiectomy. Pts were required to have progressive disease at study entry and ≥ 24 weeks of Abi treatment prior to receiving 160 mg/day ENZA. Prior chemotherapy was allowed. The primary end point was radiographic progression-free survival (rPFS). The secondary end points were overall survival (OS), prostate-specific antigen (PSA) response, and time to PSA progression. Safety was also assessed. Results: A total of215 pts were enrolled; 214 were treated with ENZA (median age, 73 years). The analysis was performed on data up to 48 weeks after the last pt started ENZA treatment. Median duration of prior Abi therapy was 54 weeks. The median duration of ENZA treatment was 5.7 months: 12 months in PSA responders and 4.6 months in non-PSA responders. 16% of pts received treatment for ≥ 1 year. The most common reason for treatment discontinuation was disease progression (65%). Median rPFS was 8.1 months (95% CI 6.1, 8.3). Median OS was not reached in the overall population and 75% of pts were alive 1 year after treatment initiation. PSA response (confirmed or unconfirmed) rate was 26.5% (48/181). The median time to PSA progression was 5.7 months (95% CI 5.6, 5.8). The overall objective response rate in pts with measurable disease at study entry was 12%. The most common treatment emergent adverse events (TEAEs) were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). ENZA was primarily discontinued due to TEAEs in 8% of pts. No seizures were reported. Conclusions: In this study, ENZA remained active in pts with mCRPC previously treated with Abi. Median rPFS in pts with prior chemotherapy was consistent with previously reported data of ENZA in pts with mCRPC and prior chemotherapy/Abi therapy.Reported TEAEs were consistent with the known safety profile of ENZA. Clinical trial information: NCT02116582.

TCTP Has a Crucial Role in the Different Stages of Prostate Cancer Malignant Progression.

Prostate cancer (PC) is the second most common cause of cancer-related mortality in men in the western world after lung cancer. Many patients are not candidates for resection given the advanced stage of their cancer. The primary treatment for advanced PC is the castration therapy which supresses the production of androgens, hormone that promotes PC growth. Despite the efficiency of the castration therapy, most patients develop castration resistant disease which remains uncurable. Clearly, novel approaches are required to effectively treat castration resistant PC (CRPC). New strategies that identify the molecular mechanisms by which PC becomes resistant to conventional therapies may enable the identification of novel therapeutic targets that could improve clinical outcome. Recent studies have demonstrated the implication of TCTP's over-expression in PC and CRPC, and its role in resistance to treatment. TCTP's interaction with p53 and their negative feedback loop regulation have also been described to be causal for PC progression and invasion. A novel nanotherapy that inhibits TCTP has been developed as a new therapeutical strategy in CRPC. This chapter will highlight the role of TCTP as new therapeutic target in PC, in particular, therapy-resistant advanced PC and report the development of novel nanotherapy against TCTP that restore treatment-sensitivity in CRPC that deserve to be tested in clinical trial.

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression.

Castration therapy in advanced prostate cancer eventually fails and leads to the development of castration-resistant prostate cancer (CRPC), which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated the expression of nuclear receptor corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens. NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with the loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets. NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1-regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In the mouse, NCOR1 is required for bicalutamide-dependent regulation of a subset of the AR target genes. In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo Clin Cancer Res; 22(15); 3937-49. ©2016 AACR.

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation.

Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCδ silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCδ seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/β-catenin pathway. PKCδ silencing induces activation of Wnt/β-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3β inactivation and consequently in the stabilization of β-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/β-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCδ. Finally, we observe that high Gleason score prostate tumors lose PKCδ expression and this correlates with higher activation of β-catenin, inactivation of GSK3β, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/β-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCδ expression. Mol Cancer Ther; 15(7); 1713-25. ©2016 AACR.

BISPHOSPHONATES IN PROPHYLAXIS OF SKELETAL-RELATED ADVERSE EVENTS IN PATIENTS WITH CASTRATION-REFRACTORY PROSTATE CANCER

Prostate cancer (PC) is one of the most urgent problems of modern oncourology. Morbidity and mortality from this disease in theRussian Federationin recent years has been steadily increasing. Including the number of patients with metastatic and refractory to castration therapy forms of the disease is increasing. Currently, the main method of treatment of patients with metastatic prostate cancer is palliative hormone therapy (HT). Patients who have progression of tumor process, with lingering castration levels of testosterone, transferred to the stage of so-called castrate-resistant prostate cancer (CRPC). The prognosis in this group of patients is extremely unfavorable, not only because of the progression of cancer, but of complications associated primarily with the presence of bone metastases. Prevention of development of serious complications such as pathological fractures, spinal cord compression is an extremely important issue. The article presents a review of studies, the sanctifying of the problem of prevention of development of bone complications in patients with CRPC. We resent the results of large studies, including those conducted in our country demonstrated the effectiveness zoedronic acid in patients with CRPC and the presence of bone metastases.

CYP17 inhibitors in prostate cancer: latest evidence and clinical potential.

Since androgen signaling plays a pivotal role in the proliferation and metastasis of prostate cancer, androgen deprivation therapy (ADT) or castration therapy is considered the backbone of treatment for newly diagnosed metastatic prostate cancer. However, almost all men experience disease progression on ADT to a state known as metastatic castration-resistant prostate cancer (mCRPC), which continues to be driven by intratumoral androgen synthesis or androgen receptor signaling. Hence, the extragonadal ablation of androgen synthesis from pregnane precursors holds much promise. An inhibitor of cytochrome P450 17α-hydroxy/17,20-lyase (CYP17) enzymes, abiraterone acetate, has already been approved for men with mCRPC. Newer CYP17 inhibitors continue to be developed which are either more selective or have concomitant inhibitory actions on AR signaling. These include VT-464, orteronel, and galeterone. Herein, we focus on the molecular mechanism of action, efficacy, latest evidence, and clinical potential of CYP17 inhibitors in prostate cancer.

DEVELOPMENT AND CLINICAL EFFECTIVENESS OF ANTIANDROGENS IN THE TREATMENT OF ADVANCED PROSTATE CANCER

Prostate cancer (PCa) is a hormonsensitive tumor. Due to the discovery of the androgen receptor (AR) it became possible to implement the antiandrogens as drugs blocking testosterone Binding to the AR into routine clinical practice. There have been discovered several generations of the antiandrogens over the years and the possibility of using these drugs in clinical practice has significantly changed. First generations of the antiandrogens (cyproterone, flutamid, bicalutamid) are used mainly for the treatment of advanced hormonsensitive PCa in combination with castration therapy. However these drugs do not increase survival in patients with PCa and are not indicated in terms of castration resistant PCa. Discovery of the enzalutamide (antiandrogen of 2’d generation), acting on the nuclear level of the tumor cell, allowed to increase significantly survival in patients with metastatic castration-resistant prostate cancer (mCRPC) and improve treatment results in patients with mCRPC. At the moment enzalutamide is being studied in combination with castration therapy in patients with hormonsensitive PCa.

Androgen deprivation therapy (castration therapy) and pedophilia: What's new.

Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile's personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects.

Abstract 2636: Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer

Abstract Metastasis is a major driver of mortality and morbidity in prostate cancer, the most common cancer type in men and the second leading cause of cancer-related deaths in the western world. To recapitulate the process in genetically engineered mice, we have developed the RapidCaP system, which uses prostate-directed viral infection to trigger focal loss of Pten and Trp53. The system provides a powerful platform for identification and validation of candidate driver genes and for efficient testing of novel therapeutics. Using this approach, we have recently identified Myc as a critical, spontaneously activated driver in Pten-negative metastatic prostate cancer. In agreement, our previous trials indicated that the Myc-suppressing Brd4 inhibitor JQ1 is ineffective towards primary disease, but causes metastatic regression. Mechanistically, this specificity correlates with the switch from Akt-driven primary to Myc-driven metastatic disease. Intriguingly, however, advanced metastases in RapidCaP do not express the androgen receptor, in spite of being of epithelial origin as shown by the Nkx3.1 prostate marker. As a consequence, metastatic disease often shows little to no response to castration therapy and invariably results in lethal disease. Therefore, we will discuss how, when and why targeting of Myc using JQ1 and the PI 3-Kinase pathway using NVP-BKM120 are best used to treat naïve or castration-resistant metastatic disease. Citation Format: Carlos E. Stahlhut, Kaitlin E. Watrud, Alexandra J. Ambrico, Hyejin Cho, Lily Wang, Jun Qi, Lewis C. Cantley, James Bradner, Lloyd C. Trotman. Myc vs. Akt therapy in RapidCap, a GEM model for metastatic prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2636. doi:10.1158/1538-7445.AM2015-2636

Progesterone receptor expression during prostate cancer progression suggests a role of this receptor in stromal cell differentiation.

The progesterone receptor, like the androgen receptor, belongs to the steroid receptor superfamily. Our previous studies have reported that the PR is expressed specifically in prostate stroma. PR inhibits proliferation of, and regulates cytokine secretion by stromal cells. However, PR protein expression in cancer-associated stroma during prostate cancer progression has not been profiled. Since the phenotypes of prostate stromal cells change dynamically as tumors progress, whether the PR plays a role in regulating stromal cell differentiation needs to be investigated. Immunohistochemistry assays measured PR protein levels on human prostate tissue microarrays containing 367 tissue cores from benign prostate, prostate tumors with different Gleason scores, tumors under various durations of castration therapy, and tumors at the castration-resistant stage. Immunoblotting assays determined whether PR regulated the expression of alpha smooth muscle actin (α-SMA), vimentin, and fibroblast specific protein (FSP) in human prostate stromal cells. PR protein levels decreased in cancer-associated stroma when compared with that in benign prostate stroma. This reduction in PR expression was not correlated with Gleason scores. PR protein levels were elevated by castration therapy, but reduced to pre-castration levels when tumors progressed to the castration-resistant stage. Enhanced PR expression in human prostate stromal cells increased α-SMA, but decreased vimentin and FSP protein levels ligand-independently. These results suggest that PR plays an active role in regulating stromal cell phenotypes during prostate cancer progression.

PII-LBA4 TERRAIN TRIAL: PROSTATE-SPECIFIC ANTIGEN KINETICS AND QUALITY OF LIFE RESULTS OF ENZALUTAMIDE VERSUS BICALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

PII-LBA4 TERRAIN TRIAL: PROSTATE-SPECIFIC ANTIGEN KINETICS AND QUALITY OF LIFE RESULTS OF ENZALUTAMIDE VERSUS BICALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Management of patients with castration-resistant metastatic prostate cancer

Prostate cancer belongs to the most common malignant tumors in males. Almost in all patients in advanced stage, disease progression occurs despite of castration therapy. Initial treatment of metastatic disease is androgen deprivation therapy. In the case of castration-resistant disease development in asymptomatic patients, it is a combination of abiraterone acetate plus prednisone and in symptomatic patients docetaxel with prednisone are considered gold standards at the present time. The aim of therapy must be assurance of adequate quality of life, pain reduction and survival improvement. The paper presents an overview of current castration-resistant metastatic prostate cancer treatment.

NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer

Castration resistance is a major issue during castration therapy for prostate cancer and thus more effective treatment are needed for castration-resistant prostate cancer (CRPC). NDRG2 (N-Myc downstream regulated gene 2), a recently identified tumor suppressor, was previously shown to inhibit the proliferation and invasion of prostate cancer, but whether NDRG2 is involved in CRPC remains to be known. Because androgen receptor (AR) axis plays an important role in castration resistance, we evaluate the role of NDRG2 in AR signaling and CRPC. Immunohistochemistry examination of prostate cancer tissues demonstrated that the expression of NDRG2 is negatively correlated with that of AR and c-Myc. Furthermore, AR negatively regulates NDRG2, as well as alters levels of c-Myc and prostate specific antigen (PSA). Forced expression of NDRG2 significantly inhibits the in vitro growth of androgen-dependent and castration-resistant prostate cancer cells; this was accompanied by alterations in PSA, but not by those of AR and c-Myc. Finally, by mimicking castration therapy in a xenograft mouse model, we showed that lentivirus-mediated NDRG2 overexpression efficiently overcomes castration resistance. Thus, by acting as a negative regulator downstream of AR, NDRG2 may emerge as a potential therapy molecule for CRPC.