Androgen Receptor Research Articles

In silico discovery of potential androgen receptor and cytochrome P450 17A1 inhibitors from Camellia sinensis for prostate cancer treatment

Prostate cancer is the second most prevalent cancer among men worldwide. Despite the significant research into its therapeutics, the current treatments remain expensive with side effects. Hence, there is a significant need for new therapeutic solutions. Thus, this study aimed to investigate the potential of bioactive compounds from Camellia sinensis as inhibitors of the androgen receptor (AR) and Cytochrome P450 17A1 (CYP17A1), offering a novel approach for prostate cancer treatment. The bioactive compounds from C. sinensis were obtained from Dr. Duke's Phytochemical and Ethnobotanical Database (DPED). The target proteins were obtained from Protein Data Bank (PDB) and prepared using Biovia Discovery Studio 2021. Active sites of the target proteins were identified using the Computed Atlas of Surface Topography of Proteins 3.0 (CASTp 3.0) database, and molecular docking analysis were conducted using the Autodock Vina plugin on PyRx software. Druglikeness and ADMET prediction were assessed using SwissAdme, admetSAR2.0, and Protox II, while molecular dynamics simulation and Molecular Mechanics-Generalized Born Surface Area analysis were performed using the Schrodinger LLC Desmond/Prime program. Out of the 117 phytocompounds retrieved, 25 phytocompounds were non-carcinogenic and positive for AR binding, while more than half showed non-promiscuity in inhibiting cytochrome variants. All 25 compounds exhibited lower binding affinity against AR and CYP17A1 compared to the controls. Specifically, Theaflavine-3,3′-digallate, Epitheaflagallin 3-O-gallate, and Gallocatechin gallate formed the best complexes with AR, while Thearubgin, Theasinensin B, and Theaflavin monogallates exhibited the most favorable interactions with CYP17A1. Additionally, these compounds showed remarkable druggability qualities. Molecular dynamics simulation validated that Gallocatechin gallate, Epitheaflagallin 3-O-gallate formed excellent stability with AR while Thearugbin and Theaflavin monogallates also exhibited commendable stability with CYP17A1 protein. Thus, the bioactives are recommended for further studies to test efficacy and toxicity.

Friend or foe? Deciphering androgen receptor action to improve bipolar androgen therapy for prostate cancer

Inhibiting the activity of the androgen receptor (AR) is the cornerstone treatment for advanced prostate cancer. AR-targeted therapies are highly effective in slowing disease progression but are not curative and the resultant disease state, termed castration-resistant prostate cancer, is associated with significant patient morbidity and mortality. In most cases, resistance to these therapies arises due to alterations that reactivate the AR signalling axis. Interestingly, it has long been recognised that potent activation of AR with supraphysiological levels of androgens can suppress prostate cancer growth in both preclinical models and patients. This intriguing paradox – where both inhibition and activation of AR have anti-cancer effects – is now being harnessed clinically in the form of bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses how our maturing understanding of these mechanisms is influencing the clinical deployment of BAT.

Characterization of the Peroxisomal Proteome and Redox Balance in Human Prostate Cancer Cell Lines.

Prostate cancer (PCa) is associated with disruptions in cellular redox balance. Given the intricate role of peroxisomes in redox metabolism, we conducted comprehensive proteomics analyses to compare peroxisomal and redox protein profiles between benign (RWPE-1) and malignant (22Rv1, LNCaP, and PC3) prostate cell lines. Our analyses revealed significant enrichment of the "peroxisome" pathway among proteins notably upregulated in androgen receptor (AR)-positive cell lines. In addition, catalase (CAT) activity was consistently higher in these malignant cell lines compared to RWPE-1, which contrasts with previous studies reporting lower CAT levels and increased H2O2 levels in PCa tissues compared to adjacent normal tissues. To mimic this clinical scenario, we used RNA interference to knock down CAT expression. Our results show that reduced CAT levels enhanced 22Rv1 and LNCaP cell proliferation. R1881-induced activation of AR, a key driver of PCa, increased expression of the H2O2-producing peroxisomal β-oxidation enzymes acyl-coenzyme A oxidase 1 and 3, reduced CAT expression and activity, and elevated peroxisomal H2O2 levels. Considering these changes and other antioxidant enzyme profile alterations, we propose that enhanced AR activity in PCa reduces CAT function, leading to increased peroxisomal H2O2 levels that trigger adaptive stress responses to promote cell survival, growth, and proliferation.

Targeted Therapy in Salivary Gland Cancer: Prevalence of a Selected Panel of Actionable Molecular Alterations in a German Tertiary Referral Center Patient Cohort.

Salivary gland carcinomas (SGC) are a heterogeneous group of malignancies, with 24 subtypes defined by the World Health Organization (WHO). The standard of therapy is surgical resection, with adjuvant radiotherapy in most cases. However, disease recurrence (R) or metastasis (M) is common and no active systemic therapies are currently available for RM-SGC resulting in a 5-year survival rate of only 20%. Overall, 55 SGC patients with seven different histological tumor subtypes were included in this study. formalin-fixed paraffin-embedded (FFPE) tissue samples were used for immunohistochemical (IHC) staining targeting HER2/neu, androgen receptor (AR), PD-L1, EGFR, panTRK, and TROP2. Fluorescence in situ hybridization (FISH) was performed for detecting HER2/neu amplifications and NTRK1/2/3 translocations in selected cases with relevant HER2/neu and panTRK protein expression, respectively. IHC and FISH results were correlated with patients' clinical and histopathological data. The overall prevalence of druggable molecular alterations, defined as an immunoreactive score ≥ 9 in at least one of the analyzed targets, was 54.4% with the highest percentage in oncocytic carcinomas (100%) and lowest percentage in acinic cell carcinomas (10%). EGFR overexpression proved to be the most common alteration (32.7% of cases) followed by overexpression of TROP2 (27.3%), AR (10.9%), HER2/neu (7.3%), PD-L1 (1.8%), and panTRK (1.8%). HER2/neu amplifications were found in 50% and NTRK translocations were found in 100% of all cases with elevated Her2/neu and panTRK protein expression, respectively. Our data indicate that targeted therapy using e.g., trastuzumab deruxtecan, bicalutamide, pembrolizumab, cetuximab, entrectinib or sacituzumab govitecan might be a promising option especially for a relevant subset of patients with RM-SGC not suitable for salvage surgery. However, evidence from clinical studies regarding response rates to these therapies remains sparse, which underlines the need of multicenter clinical trials.

Effects of time-restricted feeding and weight-loaded swimming test on androgen levels and androgen receptor expression in orchiectomized male Wistar rats

Background & AimsTestosterone, vital for reproductive health and muscle development, declines with age, increasing susceptibility to conditions like diabetes, obesity and sarcopenia. Conventional hormone therapy carries risks, including elevated prostate-specific antigens and prostate cancer risk, prompting exploration of safer options like intermittent fasting (IF) and physical training (PT) which potentially boost androgen in certain cases. However, their combined impacts on testosterone remain underexplored. This study aimed to assess the individual and combined effects of IF and PT on androgen and androgen receptor (AR) levels. MethodsForty male Wistar rats were divided into five groups (n = 8 each): negative control (NC) receiving food ad libitum without orchiectomized, positive control (PC) receiving daily testosterone enanthate injections, IF with 16/8 time-restricted feeding, PT with 1-hour forced swimming sessions, and combined IF+PT. After 8 weeks, DHEA and testosterone levels, AR expression, gastrocnemius muscle histology, and body weight were assessed. ResultsIn comparison to the NC group (429.40 ± 26.86 g), body weight in the IF (348.90 ± 15.94 g, PT (391.40 ± 16.35 g), and IF+PT groups, (360.90 ± 29.90 g) was significantly lowered (p < 0.05) after 8 weeks of study. The muscle fiber cross-sectional area in the IF (2968 μm2; IQR 1995-4053 μm2), PT (2956 μm2; IQR 2089-4371 μm2), and IF+PT groups, (3389 μm2; IQR 2260-4596 μm2) was significantly greater than the NC group (2508 μm2; IQR 1800-3567 μm2. p < 0.05) after the study. DHEA levels significantly increased in the PT and IF+PT groups (375.01 ±32.55 ng/μL and 420.00 ± 24.50 ng/μL, respectively) compared to the NC group (257.09 ± 67.79 ng/μL, p < 0.05). However, neither IF nor PT, alone or in combination, resulted in improvements in testosterone levels or AR expression in the gastrocnemius muscle. with testosterone levels remained unchanged. ConclusionIF, PT, and IF+PT demonstrated potential effects on improving androgen levels, managing weight, and enhancing muscle growth, with IF+PT emerging as the most effective intervention. Despite these positive outcomes, the lack of impact on AR expression and testosterone levels suggests the need for further research to elucidate the underlying mechanisms and potential clinical applications for managing androgen deficiency through these interventions.

The Decreased Proliferation Capacity of Cardiomyocytes Induced By Androsterone Is Mediated By the Interactions Between Androgen Receptor and Retinoblastoma Protein.

Our previous study has demonstrated that the decline in cardiomyocytes proliferation capacity induced by maternal androgen excess was mainly attributed to the accumulation of androsterone in the heart. However, the underlying mechanism by which androsterone inhibits cardiomyocytes proliferation remains unknown. In this study, pregnant mice were injected subcutaneously daily with dihydrotestosterone (DHT) from gestational day (GD) 16.5 to GD18.5. On GD18.5, fetal heart tissue was dissected and used for analyzing androgen receptor (AR) levels. H9c2 cells and primary cardiomyocytes, isolated from fetal hearts, were applied to investigate the mechanism. H9c2 cells under androsterone treatment were subjected to RNA sequencing analysis and the results showed that genes were primarily enriched in cell cycle and DNA replication pathways. Elevated AR levels were observed in fetal cardiac tissue in the maternal DHT-treated group. Androsterone treatment increased the ratio of nuclear AR and cytoplasmic AR both in H9c2 cells and primary cardiomyocytes. The ablation and overexpression of AR can mildly reverse and aggravate cell cycle arrest induced by androsterone, respectively. ChIP-qPCR analysis suggested that AR can directly repress cell cycle and DNA replication-related gene expression, which was mediated by the recruitment of retinoblastoma protein (Rb). The repression of cell proliferation in response to androsterone was alleviated partly through the downregulation of Rb by siRNA transfection. In conclusion, AR repression to cell cycle and DNA replication-related gene expression, mediated by recruitment of Rb, may be one of the potential mechanisms of cell cycle arrest in cardiomyocytes induced by androsterone.

Integrated single-cell transcriptomic analyses identify a novel lineage plasticity-related cancer cell type involved in prostate cancer progression

Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging. Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples=3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples=93, cells=222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, invitro and invivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings. We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype. Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa. This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

Variations in metabolites content and bioactivity to regulate biomarkers of benign prostatic hyperplasia according to the growth stages of Sida rhombifolia

It has been reported that the secondary metabolites produced by plants are influenced by genetic diversity and growth conditions, resulting in significant variations in chemical content even within the same species. In the previous study searching for bioactive materials from plants to improve benign prostatic hyperplasia (BPH), it was found that the methanolic extract of Sida rhombifolia in the family of Malvaceae exhibited the excellent inhibition on the expressions of 5-alpha reductase type 2 (5αR2) and androgen receptor (AR) in human prostate cells. In this study, we aimed to evaluate the change in the contents of major components of S. rhombifolia and the activity of improving BPH according to the growth stages of S. rhombifolia. Plant growth characteristics including plant height, stem diameter, leaf length, leaf width, and number of leaves were examined at intervals of approximately 15 days for 51 days. The contents of 20-Hydroxyecdysone and α-Ecdysone, the main constituents contained in S. rhombifolia on each day after transplantation (DAT) were analyzed using LC-ESI-MS/MS. The inhibitory activities of S. rhombifolia stems or leaves at each DAT on the expressions of AR, 5αR2, proliferating cell nuclear antigen (PCNA) and prostate specific antigen (PSA), were evaluated in human originated prostate cells, RWPE-1 and LNCaP cells activated by Testosterone propionate (TP). Considering the yield of the raw materials, the contents of metabolites, and the bioactivities, it was suggested that the appropriate collection period for S. rhombifolia as a bioactive material to improve BPH might be after 90 DAT.

Maternal Androgens in Dominant Meerkats (Suricata suricatta) Reduce Juvenile Offspring Health and Survivorship.

In oviparous vertebrates, maternal androgens can alter offspring immune function, particularly early in development, but the potential for negative health effects of maternal androgens in mammals remains unclear. We investigated the relation between maternal androgens, particularly in late gestation, and offspring health in the meerkat (Suricata suricatta) by comparing offspring from (a) normative dominant and subordinate matrilines, whose dams naturally express high versus lower circulating androgen concentrations, respectively, and (b) normative dominant and antiandrogen-treated dominant matrilines, whose dams' androgen function was intact versus blocked owing to experimental antagonism of the latter's androgen receptors (using Flutamide). Foetal offspring thus experienced three different endocrine environments ('high', 'lower' and 'blocked' androgens) late in prenatal development. We assessed parasitism, immune function, sex steroid concentrations and survivorship in these three offspring groups, both during juvenility and early adulthood. The juvenile offspring of subordinate control and dominant treated dams generally had lower intensities of parasite infections and greater immune function than did their peers from dominant control dams-patterns not found in adult offspring, or in relation to the offspring's concurrent hormone concentrations. Survivorship to adulthood was greatest in the progeny of treated dams. Descendants of dominant female meerkats-those in the 'high' prenatal androgen category-suffered increased parasitism and decreased immunocompetence as juveniles, as well as reduced survivorship relative to antiandrogen-exposed peers, providing evidence in mammals that maternal androgens can negatively impact offspring health and survival. These intergenerational, androgen-mediated, health effects represent early costs imposed by female intrasexual competition and its associated selection pressures.

A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients’ clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6±18.6%). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7+ patients demonstrated a worse 7-year DFS (22.7±17.7% and 20±17.9%) and overall survival (63.6±14.5% and 40±21.8%). Importantly, 80% of the nuclear ARv7+ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain

Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in female mice. PerspectiveThis article presents novel mechanisms testosterone’s protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain.

Defining the clinical value of circulating splicing factors in prostate cancer: SRRM1 as a novel predictive biomarker and exploitable therapeutic target

Prostate cancer (PCa) is the second most common cancer among men worldwide. The main screening tool remains the prostatic specific antigen (PSA), which shows significant limitations including poor sensitivity/specificity. Therefore, establishing accurate non-invasive diagnostic biomarkers remains an unmet clinical need in PCa. In this context, the splicing process dysregulation represents a PCa hallmark. Herein, plasma SNRNP200, SRSF3, and SRRM1 levels, previously identified to play a pathophysiological role in PCa, were determined in control individuals (n=40) and PCa patients (n=166). We found that plasma SNRNP200 and SRRM1 levels were elevated in PCa patients and discriminated between control individuals and PCa patients. High plasma SRRM1 levels were associated with a shorter castration-resistant PCa-free survival and correlated with Androgen-Receptor (AR)/AR-splicing variant V7 expression levels and activity in PCa tissues. Therefore, the functional and molecular effects of in-vivo SRRM1 silencing were then tested in 22Rv1-derived xenograft tumors. In-vivo SRRM1 silencing reduced aggressiveness features and altered AR/AR-V7 activity. Altogether, our data reveal that SRRM1 holds potential as a non-invasive diagnostic and prognostic biomarker, and novel therapeutic target in PCa, offering a clinically relevant opportunity worth to be explored in humans.

Surgical Castration as an Alternative to Improve Systemic Treatment for Advanced Prostate Cancer: A Window of Opportunity for Developing Countries.

The Brazilian Public Health System (BPHS) serves approximately 71,730 patients with prostate cancer (PC) every year for which androgen deprivation therapy (ADT) is the primary treatment for patients with advanced hormone-sensitive prostate cancer (aHSPC). Androgen receptor pathway inhibitors (ARPIs) are not accessible through the BPHS. Using the BPHS as a model, this study assesses the long-term economic effect of surgical versus medical castration in aHSPC treatment to strategize cost reduction and the incorporation of ARPI in developing countries. Data of patients with aHSPC (ie, TxN1M0 ineligible for local treatment or TxNxM1) from the BPHS database were analyzed from January 1, 2011, to December 31, 2021, using the TECHTRIALS artificial intelligence platform. The main outcomes were quantitative and descriptive analyses as well as a cost analysis of surgical versus chemical castration. Of the 274,519 patients with aHSPC who received active treatment during the 11-year study period, 90% (n = 246,683) underwent chemical castration and 10% (n = 27,836) underwent bilateral subcapsular orchiectomy (BSO). The median duration of chemical castration was 28 months. The BPHS spent an estimated total of $665,552,091.40 US dollars (USD) on chemical castration and $5,939,348.47 USD on BSO, respectively. The cost per patient was $2,698 USD and $213.37 USD for chemical castration and BSO, respectively. Hypothetically, if all patients with aHSPC had undergone BSO, the total direct cost for the BPHS would have been $42,774,832.20 USD, saving $622,777,259.20 USD over 11 years, making it possible to offer low-dose abiraterone to 65% of aHSPC patients. On the basis of this extensive financial analysis from the world's largest public health system database, BSO appears to be a valuable alternative to chemical castration for treating aHSPC. In resource-limited environments, the cost savings from using BSO may allow access to drugs that will improve survival such as ARPIs.

P087 Comprehensive evaluation of androgen receptor pathway inhibitor monotherapy in prostate cancer: Safety, oncologic outcomes, and quality of life – a systematic review and meta-analysis

P087 Comprehensive evaluation of androgen receptor pathway inhibitor monotherapy in prostate cancer: Safety, oncologic outcomes, and quality of life – a systematic review and meta-analysis

An Overview of Commonly Used Natural Alternatives for the Treatment of Androgenetic Alopecia, with Special Emphasis on Rosemary Oil.

Androgenetic alopecia is a chronic dermatological condition in which genetically predisposed individuals undergo progressive hair loss secondary to the effects of circulating androgens. It has been well documented that dihydrotestosterone binds to the androgenic receptors prevalent in the scalp, thus inducing miniaturization of the hair follicle. To date, the only FDA approved medications for the treatment of androgenetic alopecia are finasteride and minoxidil. A plethora of studies have been conducted testing the efficacy of various herbal compounds, but additional research is needed to further establish the concrete efficacy of such natural remedies in treating androgenetic alopecia. Of late, rosemary oil has gained mass popularity as a promising natural alternative. This review article will not only provide a detailed background on this ancient herbal component but will additionally overview all other major herbal alternatives including peppermint oil, tea tree oil, green tea, pumpkin seed oil, saw palmetto, and lavender oil and will summarize the latest clinical studies, which have tested their efficacy for the management of androgenetic alopecia.

Multivariable models of outcomes with [177Lu]Lu-PSMA-617: analysis of the phase 3 VISION trial

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. Novartis.

Changes in the treatment landscape of metastatic hormone-sensitive prostate cancer following approval of upfront androgen receptor signaling inhibitors: A multicenter study.

A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone-sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan-Meier method was used to assess oncological outcomes, including time to castration-resistant prostate cancer (CRPC), progression-free survival 2 (PFS2, duration from initial treatment to tumor progression during second-line treatment), cancer-specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Kaplan-Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grades 3-4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. Initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first-line treatment option given its superior oncological outcomes.

Recent advances in basic research on prostate cancer: Where we are heading?

In the over 80 years since androgens were found to play a pivotal role in prostate cancer (PCa) progression, androgen deprivation therapy (ADT) has been a cornerstone in treating advanced PCa. Castration-resistant PCa persists, however, with some of these tumors evolving to androgen receptor (AR)-independent forms like neuroendocrine PCa. The development of novel diagnostic and therapeutic approaches to PCa is therefore crucial. This review provides an overview of recent basic research in PCa, focusing on two main areas: PCa cells and their tumor microenvironments. The first section describes current knowledge on the intricate mechanisms of AR signaling pathways, emphasizing the roles of coactivators and chromatin state alterations in gene regulation. Genomic analyses have revealed recurrent mutations and copy number alterations critical for precision medicine. Liquid biopsy has become a promising tool for real-time tumor monitoring, identifying genetic alterations in circulating-tumor DNA or extracellular vesicles. The second section describes the tumor microenvironment of PCa, highlighting its immunosuppressive landscape and the potential of combining ADT with immunotherapy. Advanced techniques, including single-cell RNA sequencing and spatial transcriptomics offer insights into cellular heterogeneity and interactions within the tumor microenvironment, paving the way for novel therapeutic strategies. Integration of these diverse research areas will provide a comprehensive understanding of the current state and future directions of PCa research, underscoring the importance of personalized medicine and the dynamic nature of cancer treatment strategies.

PARP inhibitors in prostate cancer: clinical applications.

Despite recent advancements in the treatment of metastatic castrate-resistant prostate cancer (mCRPC), this disease remains lethal. A novel family of targeted pharmaceuticals known as poly-ADP-ribose polymerase (PARP) inhibitors has been developed to treat mCRPC patients with homologous recombination repair (HRR) gene alterations. The FDA recently approved olaparib and rucaparib for treating mCRPC patients with HRR gene alterations. Ongoing trials are investigating combination therapies involving PARP inhibitors combined with radiation, chemotherapy, immunotherapy, and androgen receptor signaling inhibitors (ARSIs) to improve the effectiveness of PARP inhibitors and broaden the range of patients who can benefit from the treatment. This review provides an overview of the development of PARP inhibitors in prostate cancer and analyzes the mechanisms underlying their resistance.

Untangling the role of tau in sex hormone responsive cancers: lessons learnt from Alzheimer's disease.

Tubulin associated unit has been extensively studied in neurodegenerative diseases including Alzheimer's disease (AD), whereby its hyperphosphorylation and accumulation contributes to disease pathogenesis. Tau is abundantly expressed in the central nervous system but is also present in non-neuronal tissues and in tumours including sex hormone responsive cancers such as breast and prostate. Curiously, hormonal effects on tau also exist in an AD context from numerous studies on menopause, hormone replacement therapy, and androgen deprivation therapy. Despite sharing some risk factors, most importantly advancing age, there are numerous reports from population studies of, currently poorly explained inverse associations between cancer and Alzheimer's disease. We previously reviewed important components of the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signalling pathway and their differential modulation in relation to the two diseases. Similarly, receptor tyrosine kinases, estrogen receptor and androgen receptor have all been implicated in the pathogenesis of both cancer and AD. In this review, we focus on tau and its effects in hormone responsive cancer in terms of development, progression, and treatment and in relation to sex hormones and PI3K/Akt signalling molecules including IRS-1, PTEN, Pin1, and p53.