Showing papers on "Castration Resistance published in 2015"

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects.

Abstract: Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.

Autocrine activation of CHRM3 promotes prostate cancer growth and castration resistance via CaM/CaMKK-mediated phosphorylation of Akt

Abstract: Purpose: Although a previous study reported nerve ending-derived acetylcholine promoted prostate cancer invasion and metastasis by regulating the microenvironment of cancer cells, the present study aims to determine whether there is autocrine cholinergic signaling in prostate epithelial cells that promotes prostate cancer growth and castration resistance. Experimental Design: In this study, immunohistochemistry (IHC) was performed to detect protein expression in mouse prostate tissue sections and human prostate cancer tissue sections. Subcutaneously and orthotopically xenografted tumor models were established to evaluate the functions of autocrine cholinergic signaling in regulating prostate cancer growth and castration resistance. Western blotting analysis was performed to assess the autocrine cholinergic signaling-induced signaling pathway. Results: We found the expression of choline acetyltransferase (ChAT), the secretion of acetylcholine and the expression of CHRM3 in prostate epithelial cells, supporting the presence of autocrine cholinergic signaling in the prostate epithelium. In addition, we found that CHRM3 was up-regulated in clinical prostate cancer tissues compared to adjacent non-cancer tissues. Over-expression of CHRM3 or activation of CHRM3 by carbachol promoted cell proliferation, migration and castration resistance. On the contrary, blockading CHRM3 by shRNA or treatment with darifenacin inhibited prostate cancer growth and castration resistance both in vitro and in vivo. Furthermore, we found that autocrine cholinergic signaling caused calmodulin/calmodulin-dependent protein kinase kinase (CaM/CaMKK)-mediated phosphorylation of Akt. Conclusions: These findings suggest that blockade of CHRM3 may represent a novel adjuvant therapy for CRPC.

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Abstract: Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-β (TGF-β) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-β) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-β inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

Metastatic castration-resistant prostate cancer: time for innovation

Abstract: Androgen deprivation is the mainstay of advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). The understanding of the biology of CRPC and the evidence that CRPC still remains driven by androgen receptor signaling led to the discovery of new therapeutic targets. In the last few years, large Phase III trials showed improvements in survival and outcomes and led to the approval of a CYP17 inhibitor (abiraterone), an androgen receptor antagonist (enzalutamide), the taxane cabazitaxel, an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T). This article describes the molecular mechanisms underlying castration resistance, discusses recent and ongoing trials and offers some insights into identifying the best sequence of new drugs.

Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations.

Abstract: Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.

Serum follicle-stimulating hormone levels predict time to development of castration-resistant prostate cancer.

Abstract: Introduction: Treatment of advancing prostate cancer focuses on blocking the activation of the androgen receptor with resultant prolonged perturbation of the hypothalamic-pituitary-gonadal axis. Androgen deprivation therapy (ADT) is marked, however, by eventual progression to castration- resistant prostate cancer (CRPC). Emerging evidence has postulated that follicle-stimulating hormone (FSH) may lead to proliferative and mutagenic responses of prostate cancer. We investigated the association of serum FSH and time to castration resistance. Methods: This was a single-centre retrospective study assessing serum FSH levels of patients undergoing ADT for advancing prostate cancer. The primary outcome was time of ADT initiation to the development of CRPC. For each patient on treatment and with castrate levels of testosterone, the maximum FSH value between ADT commencement and CRPC was identified and recorded. FSH was analyzed as a continuous and categorical variable. Cox multivariate regression in a step-wise fashion was used to explore the association between FSH levels and time to CRPC. Results: From a database of 323 prostate cancer patients actively managed with ADT, 103 men had a documented FSH value while castrate, with 45 men progressing to CRPC. The mean ± standard deviation maximum FSH value of these patients was 6.66 ± 4.22 mIU/mL (range: 1.5–28.1). The mean duration from ADT commencement to CRPC was 3.03 ± 0.34 years (range: 0.36–9.71). Univariate analysis suggested a trend of a negative correlation between FSH values and time to castrate resistance. A FSH value of less than or equal to the lowest tertile (4.8 mIU/mL) was associated with a longer time to CRPC (hazard ratio 0.46; p = 0.006). In the Cox regression analysis, elevated FSH was associated with a shorter duration time to CRPC (p = 0.03). Conclusions: This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.

Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth.

Abstract: Prostate cancer is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated prostate cancer initially respond to androgen deprivation therapy (ADT), but virtually all patients will relapse and develop incurable castration-resistant prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating prostate cancer cell growth led to our discovery that checkpoint kinase 2 (CHK2) knockdown dramatically increased prostate cancer growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2 depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects prostate cancer proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. In addition, we provide evidence that CHK2 physically associates with the AR and that cell-cycle inhibition increased this association. Finally, IHC analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and prostate cancer growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation.

Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass

Abstract: SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs.

Metastasis initiating cells in primary prostate cancer tissues from transurethral resection of the prostate (TURP) predicts castration‐resistant progression and survival of prostate cancer patients

Abstract: BACKGROUND We previously reported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naive patients can predict the progression to castration resistance and the overall survival of PC patients. Prostate 75:1312–1321, 2015. © 2015 Wiley Periodicals, Inc.

Prostate cancer: AR splice variant dimerization-clinical implications.

Abstract: Androgen receptor splice variants might be associated with castration resistance in prostate cancer as well as resistance to hormonal therapies including abiraterone and enzalutamide. New data demonstrate that splice variants can form dimers with each other as well as with the full-length androgen receptor, and that dimerization is required for androgen-independent transcriptional activation of target genes.

Loss of Wave1 gene defines a subtype of lethal prostate cancer

Abstract: Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence. Further analysis of primary vs. castration resistant prostate cancer indicate that disruption of WAVE complex gene expression, and particularly WAVE1 gene (WASF1) loss, is also associated with castration resistance, where WASF1 is frequently co-deleted with PTEN and resists androgen deprivation therapy (ADT). Hence, we propose that WASF1 status defines a subtype of ADT-resistant patients. Better understanding of the effects of WAVE pathway disruption will lead to development of better diagnostic and treatment modalities.

Concurrent Diabetes Mellitus may Negatively Influence Clinical Progression and Response to Androgen Deprivation Therapy in Patients with Advanced Prostate Cancer.

Abstract: Objective: To determine if a concurrent diagnosis of diabetes mellitus is associated with worse outcomes in advanced prostate cancer. The effect diabetes may have on the progression of advanced prostate cancer is poorly understood. Methods: Data on 148 advanced prostate cancer patients (35 with concurrent diabetes) were collected from an institutional database to obtain diabetic status, data on treatment types and durations, and PSA values before, during and after treatment. Time to castration resistance following the onset of androgen deprivation therapy (ADT) and overall survival in patients with and without diabetes were compared using univariate Cox regression analyses as the primary endpoints. Differences in PSA response to treatments were compared using chi-squared tests as a secondary endpoint. Results: With a median follow-up of 29 months, time to castration resistance did not differ significantly between patients with and without diabetes who underwent ADT. However, in a subset of patients who received ADT without radiographic evidence of metastases (N=47), those with diabetes progressed to castration-resistant disease more quickly than those without diabetes (Hazard Ratio for progression with diabetes = 4.58; 95% CI: 1.92-10.94; p = 0.0006). Also, a lower percentage of patients with diabetes undergoing ADT had PSA declines of at least 50% (p=0.17) and reached a nadir PSA <0.2 ng/mL (p=0.06). Overall survival did not differ based on diabetic status. No differences were seen in response to first-line therapy for castration-resistant prostate cancer. Conclusions: Diabetes mellitus may have a detrimental effect on progression of advanced prostate cancer, particularly in those patients without radiographic evidence of metastases. Further study is necessary to fully elucidate the effect of diabetes on prostate cancer outcomes.

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

Abstract: 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.

CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells

Abstract: Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.

Methylselenocysteine preventing castration-resistant progression of prostate cancer

Abstract: BACKGROUND Castration-resistant progression of prostate cancer after androgen deprivation therapy remains a critical challenge in the clinical management of prostate cancer. Resurgent androgen receptor activity is an established driver of castration-resistant progression, and upregulation of androgen receptor expression has been implicated to contribute to the resurgent androgen receptor activity. We reported previously that methylselenocysteine can decrease the expression and activity of androgen receptor. Here we investigated the ability of methylselenocysteine to inhibit castration-resistant progression of prostate cancer. METHODS The regrowth of LNCaP prostate cancer xenografts after castration was monitored. The levels of prostate-specific antigen in mouse serum were measured by ELISA. Tumor cell proliferation and apoptosis were analyzed via Ki-67 immunohistochemistry and TUNEL assay, respectively. Intratumoral angiogenesis was assessed by immunohistochemistry staining of vascular endothelial growth factor and CD31. RESULTS We showed that methylselenocysteine delayed castration-resistant regrowth of LNCaP xenograft tumors after androgen deprivation. This was accompanied by decreased serum levels of prostate-specific antigen, inhibition of prostate cancer cell proliferation and tumor angiogenesis, as well as downregulation of androgen receptor and induction of apoptosis in the relapsed tumors. CONCLUSIONS The present study represents the first to show the preclinical efficacy of methylselenocysteine in delaying castration-resistant progression of prostate cancer. The findings provide a rationale for evaluating the clinical application of combining methylselenocysteine with androgen deprivation therapy for the treatment of advanced prostate cancer. Prostate 75:1001–1008, 2015. © 2015 Wiley Periodicals, Inc.

The predictive value of ARv7 expression in localized prostate caner treated with abiraterone, degarelix, and bicalutamide.

Abstract: 71 Background: Androgen receptor splice variants (ARvs) are upregulated in response to castration, and can activate transcription in the absence of ligand. Recent evidence indicates that CTC ARv7 expression is an accurate predictor of absence of response to abiraterone and enzalutamide, providing strong clinical support for ARv7 upregulation as potential overarching mechanism of castration resistance. There is however limited data regarding the expression of ARv7 in clinically localized prostate cancer (CaP), and it is unknown if expression in the primary tumor is similarly predictive. We were therefore interested to determine the expression of ARv7 in high-risk disease, and correlate this with response to an abiraterone-containing castrating regimen. Methods: We performed an open label non-randomized Phase II neoadjuvant study of ‘supercastration’ in men with high-risk clinically localized CaP using an optimal 2-stage design (ACTRN12612000772842). Treatment consisted of degarelix 240/80mg q 1/12, abirate...

Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) in patients (pts) with castration-resistant prostate cancer (CRPC): PK, safety and PR testing results from the dose escalation cohort.

Abstract: 5051 Background: An urgent need exists for new therapies after progression (PD) onabiraterone (AA) and enzalutamide (ENZ). PR expression increases with castration resistance [Bonkhoff 2001]. ONA, a...

Avances en el tratamiento de cáncer de próstata resistente a la castración: énfasis en nuevas terapias hormonales

Abstract: Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as “hormone refractory”. In recent years, the concept of hormone refractoriness has been challenged and replaced by “castration resistance”, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.

Castrate Resistant Prostate Cancer: Systemic Chemotherapy and a System Problem

Abstract: Castrate resistant prostate cancer remains a significant problem, despite the introduction of many new anticancer agents in recent years. Of importance, establishing true castration resistance, confirmed biochemically, is a sine qua non of effective management. It should also be recognized that stage migration has occurred, with more patients being offered treatment for PSA-only castration-resistant disease, and with the increased radiological surveillance of patients after definitive local treatment, and the goal posts have widened due to increased emphasis on patient-reported outcomes and progression-free survival. That said, it is clear that, in addition to established cytotoxic agents, several new options of systemic therapy are active in castrate resistant prostate cancer, including ixabepilone, cabazitaxel, cabozantanib, and the current focus seems to be shifting somewhat from cytotoxic to targeted therapeutics.

Management of castration-resistant (advanced) prostate cancer (CRPC): rationale, progress and future directions.

Abstract: Background Prostate cancer is the most common solid organ cancer and the second most common cause of cancer-related deaths in Australian men. Objective The aim of our review is to provide general practitioners with up-to-date information about castration resistance and hormonal dependence in prostate cancer. We summarise the current ongoing and completed clinical trials targeting hormonal pathways in metastatic prostate cancer. Discussion The treatment paradigm of metastatic castration-resistant prostate cancer has changed markedly in the past decade and new agents targeting androgen receptor pathways have been introduced. However, the biggest challenge for clinicians is to develop guidelines to integrate these agents into clinical practice.

In-vitro mini-reporter gene used for predicating androgen receptor posttranscriptional modification sites and application thereof

Abstract: The invention relates to an in-vitro mini-reporter gene used for predicating androgen receptor posttranscriptional modification sites and an application thereof. Experiments indicate that lncRNA PCGEM1 directly decides castration resistance or recurrence and metastasis of hormones for expressing the tumours of an androgen receptor after castration by regulating the posttranscriptional modification of the isomer AR-V7(AR3) pre-mRNA of the androgen receptor; on this basis, sequences containing exons Exon3 and Exon4 of the pre-mRNA of the AR are selected to construct the mini-reporter gene through gene cloning; on one hand, the mini-reporter gene is used for predicating high-risk factors causing the hormone castration recurrence and metastasis of the tumours related to the androgen receptor, such as prostatic cancer; on the other hand, the expression and action of the specific target gene sites can be intuitively, efficiently and accurately verified and blocked through the mini-reporter gene.

Germ line predictors of response to androgen deprivation therapy in men with advanced prostate cancer.

Abstract: 162 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in advanced prostate cancer, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 47 polymorphisms (PMs) in 22 genes involved in the androgen metabolic pathway were investigated using tagging SNPs for association with time to onset of castration resistance in 144 Caucasian men diagnosed with advanced prostate cancer undergoing ADT. Linear regression was employed using Gleason score as a covariate and assessing each SNP under one of three genetic models: 1) an additive model in which the number of minor alleles contributes increasing risk (or protection), 2) a dominant model in which the presence of 1 or 2 minor alleles have the same effect, and 3) a recessive model in which the presence of 2 minor alleles are necessary. Results: PMs in 3 genes (CYP1A1, HSD17B3, and HSD17B12) were si...

Novel Functions of NF-kappaB2/p52 in Androgen Receptor Signaling in CRPC

Abstract: : Purpose: Prostate cancer is one of the leading causes of cancer-related mortality in men in the United States. Androgen receptor signaling remains active in castration-resistant prostate cancer (CRPC). Here we show that NF-kappaB2/p52 activates the androgen receptor in the absence of ligand, via modulation of microRNA such as let-7c and via activation of intratumoral steroidogenesis by induction of higher levels of steroidogenic enzymes. We also show that NFkappaB2/ p52 induces resistance to anti-androgen therapies by inducing alternative splicing of the androgen receptor to increase levels of constitutively active variants. Scope: The identification of the pathway leading to androgen receptor activation by NF- B2/p52 may have implications for therapeutic applications against CRPC. The finding that p52 induces resistance to anti-androgenic therapies may have implications in the choice of treatment regimen in CRPC. Major Findings: We showed that: Downregulation of p52 reduces intracrine androgen synthesis; p52 regulates expression of steroidogenic enzymes; p52 induces expression of AR splice variants and thereby enhances resistance of prostate cancer cells to anti-androgens; p52 regulates expression of miR-let-7c; miR-let-7c reduces expression of AR; and that the NF-kappaB2/p52:c-Myc:let-7c:Lin28 axis plays a major role in the development of castration resistance. Significance: Current research efforts focus primarily on targeting the androgen receptor in CRPC. But the persistent activation of AR has been suggested to be one of the mechanisms of development of resistance to AR-targeted therapies. Our findings show that p52 plays a significant role in the development of castration and therapy resistance.

Modified LNA oligonucleotide for targeting lncRNAs to resist AR-related tumor castration-recurrent

Abstract: The invention relates to a modified LNA oligonucleotide for targeting lncRNAs to resist AR-related tumor castration-recurrent. Researches show that the expression of PCGEM1 is highly correlated with malignancy as well as recurrence and metastasis of prostate cancers, and is highly positive correlated with the expression of an AR isoform, such as AR3 (AR-V7), and researches also prove that the PCGEM1 modifies and regulates the expression of the AR isoform, such as AR3, through alternative transcription. Based on the research results, the LNA oligonucleotide can directly target the target gene PCGEM1, can efficiently and accurately block the expression of the PCGEM1, and blocks a PCGEM1-mediated androgen receptor isoform AR3 through joint targeting, so that the castration resistance as well as recurrence and metastasis possibility of AR-related tumors subjected to hormone castration treatment can be effectively reduced. The modified LNA oligonucleotide is good in specificity and high in stability; animal experiments show that the modified LNA oligonucleotide can suppress tumor growth, and the effect is very significant.

[Prostate cancer stem cells: advances in current research].

Abstract: Prostate cancer is one of the most common malignancies threatening men's health, and the mechanisms underlying its initiation and progression are poorly understood. Last decade has witnessed encouraging progress in the studies of prostate cancer stem cells (PCSCs), which are considered to play important roles in tumor initiation, recurrence and metastasis, castration resistance, and drug resistance. Therefore, a deeper insight into PCSCs is of great significance for the successful management of prostate cancer. This article presents an overview on the location, origin, and markers of PCSCs as well as their potential correlation with tumor metastasis and castration resistance.

The Hormonal Management of Metastatic Prostate Cancer

Abstract: As many as 30 % of men treated with curative intent for localized prostate cancer will suffer a relapse, and a small number of men are diagnosed with prostate cancer which has already metastasized. For these men, androgen deprivation therapy is a highly effective treatment, although castration resistance inevitably develops. Over the last 20 years, clinical trials have yielded important advances in optimizing the use of androgen deprivation, such as the use of combined blockade versus monotherapy, and intermittent versus continuous treatment. In addition, there has been heightened awareness of the adverse consequences of androgen deprivation, specifically loss of bone mineral density, metabolic changes and cardiovascular morbidity. Future research will focus on incorporating novel agents into early treatment of metastatic prostate cancer, such as third generation androgen manipulating agents, non-androgen targeted therapies, and immune therapy.

Molecular Determinants of Hormone-Refractory Prostate Cancer

Abstract: : We have performed a high throughput, in vivo genetic screen to identify kinases that permit androgen-dependent transformed prostate epithelial cells (LHSR-AR cells) to form tumors in female animals. In addition to known prostate cancer oncogenes and mediators of androgen independence (mutated KRAS, constitutively active MEK, RAF1, ERBB2, AKT1, PIM1 and PIM2), overexpression of the Never In Mitosis A (NIMA) related kinase 6 (NEK6) reproducibly yielded androgen-independent tumors. NEK6 is overexpressed in prostate cancer cell lines compared to their normal counterparts and is overexpressed in a subset of human prostate cancers. Expression of NEK6 confers castration resistance to established tumors in male mice, and suppressing NEK6 expression restores sensitivity to castration. Castration-resistant tumors generated through NEK6 overexpression are predominantly squamous in histology and do not express androgen receptor (AR), and NEK6 does not activate AR signaling. Phosphoproteome and interactome analysis reveals the transcription factors FOXJ2 and NCOA5, as well as the kinases CK1 and YES1 to be novel substrates. The gene expression profile mediated by NEK6 overexpression in tumors from castrated mice demonstrates elements of both differentiation and immune signaling, and phosphomimic forms of FOXJ2, YES1, and CK1 (but not NCOA5) recapitulate elements of this signature, particularly CK1 with markers of squamous differentiation. These studies reveal a novel mechanism of resistance in androgen pathway independent prostate cancer (APIPC).