Androgen Deprivation Research Articles

Nodal radiotherapy for prostate adenocarcinoma recurrence: predictive factors for efficacy.

Nodes are the second site for prostate cancer recurrence. Whole-pelvic radiotherapy (WPRT) has shown superiority over nodal stereotactic body radiotherapy (SBRT) in two retrospective cohorts. We aimed to compare both modalities and assess factors associated with treatment outcomes. This retrospective multicentric cohort study included patients from five institutions spanning from 2010 to 2022. Patients had a history of prostatic adenocarcinoma classified as N0 M0 at diagnosis with a first nodal-only pelvic castration-sensitive recurrence. Failure-free survival (FFS) was defined as the time from the end of RT to the first failure event-biochemical or imaging recurrence, or death. A total of 147 patients (pts) were analyzed, mainly treated for a recurrence after initial prostatectomy (87%), with 64 (43.5%) undergoing SBRT and 83 (56.5%) undergoing WPRT. SBRT was chosen mainly for dosimetric constraints (67%) and was associated with a lower rate of concomitant androgen deprivation therapy (ADT) prescription. With a median follow-up of 68 months [inter-quartile range (IQR) = 51], FFS was significantly lower in the SBRT group (p < 0.0001). In multivariable analysis, WPRT and ADT were associated with a longer FFS. Factors associated with a longer FFS after SBRT included associated ADT, lower prostate-specific antigen (PSA) levels, a PSA doubling time >6 months, and a Gleason score <8. SBRT was associated with a lower rate of genitourinary and gastrointestinal grade ≥2 complications. For an isolated pelvic nodal prostate cancer recurrence, SBRT is associated with a shorter FFS compared to WPRT. SBRT is often more convenient for patients and leaves further pelvic salvage options available, so it can be explored as an option for well-informed patients.

Optimización de la triple terapia en el tratamiento del cáncer de próstata hormonosensible metastásico

Triple therapy with docetaxel, androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) has demonstrated survival benefits in patients with metastatic hormone-sensitive prostate cancer (mHSPC), especially in those with high-risk disease. However, once the use of ADT and docetaxel is established, guidelines do not clearly specify which ARPI is most appropriate. In this work, a literature review to identify phase III clinical trials, systematic reviews, meta-analyses, and clinical practice guidelines on triple therapy in mHSPC was carried out. Evidence and recommendations were qualitatively reviewed to provide guidelines on the most suitable ARPI based on patient risk, disease volume, and nature of metastases (synchronous or metachronous). This review aims to update the previously published consensus on the optimal pharmacological treatment for mHSPC and to expose the opinions of hospital pharmacy, urology and medical and radiation oncology experts.

MicroRNAs as Promising Therapeutic Agents Against Prostate Cancer Resistant to Castration—Where Are We Now?

MicroRNAs are a conserved class of small, tissue-specific, non-coding RNAs that regulate gene expression to preserve cellular homeostasis. Proper miRNA expression is crucial for physiological balance because it affects numerous genetic pathways, including cell cycle control, proliferation, and apoptosis, through gene expression targeting. Deregulated miRNA expression has been implicated in several cancer types, including prostate cancer (PC), acting as tumor suppressors or oncogenes. Despite the availability of promising therapies to control tumor growth and progression, effective diagnostic and therapeutic strategies for different types of cancer are still lacking. PC continues to be a significant health challenge, particularly its castration-resistant (CRPC) form, which presents major therapeutic obstacles because of its resistance to conventional androgen deprivation treatments. This review explores miRNAs’ critical roles in gene regulation and cancer biology, as well as various miRNA delivery systems, highlighting their potential and the challenges in effectively targeting cancer cells. It aims to provide a comprehensive overview of the status of miRNA research in the fight against CRPC, summarizing miRNA-based therapies’ successes and limitations. It also highlights the promise of miRNAs as therapeutic agents for CRPC, underlining the need for further research to overcome existing challenges and move these therapies toward clinical applications.

The Effect of Androgen Deprivation Therapy on the Cardiovascular System in Advanced Prostate Cancer

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study.

Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes.

BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx). We also interrogated the Caris Precision Oncology Alliance (POA) DNA (592-gene/whole exome) and RNA (whole transcriptome) next-generation sequencing databases. Algorithm for Linking Activity Networks (ALAN) was used to quantify all pairwise gene-to-gene associations. Real-world overall survival was determined from insurance claims data using Kaplan-Meier estimates.RESULTSSix APUC genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) exhibited coalescent gene behavior in a cohort of metastatic tumors (n = 208). In the Caris POA dataset, the 6 APUC genes (APUC-6) exhibited robust clustering in primary prostate (n = 4,490) and metastatic (n = 2,593) biopsies. Surprisingly, tumors with elevated APUC-6 expression had statically lower expression of AR, AR-V7, and AR signaling scores, suggesting ligand-driven disease biology. APUC-6 genes instead associated with the expression of alternative steroid hormone receptors, ESR1/2 and PGR. We used RNA expression of AR or APUC-6 genes to define 2 subgroups of tumors with differential association with hallmark pathways and cell surface targets.CONCLUSIONSThe APUC-6-high/AR-low tumors represented a subgroup of patients with good clinical outcomes, in contrast with the AR-high or neuroendocrine PCs. Altogether, measuring the aggregate expression of APUC-6 genes in current genomic tests identifies PCs that are ligand (rather than AR) driven and require distinct therapeutic strategies.FUNDINGNCI/NIH 1R37CA288972-01, NCI Cancer Center Support P30 CA077598, DOD W81XWH-22-2-0025, R01 CA249279.

Assessing racial differences in time to subsequent treatment following androgen deprivation therapy among Veterans with prostate cancer.

Background For metastatic and certain advanced prostate cancer (PC), guidelines support intensified androgen deprivation therapy (ADT) as first-line (1L) systemic treatment for improved outcomes. However, some patients receive ADT alone, leading to tumor progression requiring 2nd line therapy. Despite significant racial disparities in PC outcomes, there are no population-level studies assessing racial differences in time to subsequent treatment after 1L ADT. Methods We performed a retrospective population-level analysis to assess the association between race and time to subsequent treatment after ADT in the Veterans Affairs Health Care System. Primary outcome was time from ADT monotherapy to subsequent treatment, defined as receipt of androgen receptor pathway inhibitor (ARPI), non-steroidal first-generation anti-androgen (NSAA), chemotherapy, or other treatments. We used Cox models and Kaplan-Meier (KM) analyses to estimate subsequent treatment rates by Non-Hispanic White [NHW], Non-Hispanic Black [NHB], Hispanic and Other patients adjusted for baseline covariates. Results From 2001-2021, 141,495 PC patients received ADT alone. During median (IQR) follow-up of 51.1 (22.8, 97.2) months, 28,144 patients (20%) had subsequent treatment: 11,319 (40%) ARPIs, 12,990 (46%) NSAAs, 3,402 (12%) chemotherapy and 433 (2%) other 2nd line therapies. NHB had significantly lower subsequent treatment rates (HR = 0.82, 95%CI = 0.80-0.85) compared to NHW. Both Hispanic (HR = 0.93, 95%CI = 0.88-0.98) and Other men (HR = 0.91, 95%CI = 0.84-0.98), also had lower subsequent treatment rates. Conclusions All races examined had significantly lower rates of subsequent treatment after 1L ADT relative to NHW. Further investigation is needed to determine if these lower rates of subsequent treatment reflect lower rate of progression or undertreatment of progressing patients.

Phase 2 trial of PSMA PET CT versus planar bone scan and CT in prostate cancer patients progressing while on androgen deprivation therapy

For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6–77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

Research Progress of AR Gene Family in Prostate Cancer Therapy

Prostate cancer (PCa) is a malignancy originating from the epithelial cells of the prostate gland, strongly influenced by androgens, and is one of the most common cancers in men. Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. However, after prolonged ADT treatment, nearly all patients experience an increase in prostate-specific antigen (PSA) levels and tumor regrowth. The regrowth is primarily driven by the reactivation of androgen signaling pathways within the tumor cells, leading to the development of castration-resistant prostate cancer (CRPC). The overall survival for patients with CRPC is typically less than two years. The reactivation of androgen signaling after ADT is a key mechanism leading to the progression of CRPC. In particular, abnormal expression of androgen receptor (AR) family genes, particularly AKR1C3 and AR-V7, are beleived to play central roles in the emergence of CRPC. Beyond hormonal factors, various molecular mechanisms contribute to the development of castration resistance, such as genetic mutations and the role of the tumor microenvironment. Additionally, dysregulation of signaling pathways and interactions between tumor cells and the surrounding matrix furrher promote tumor survival and growth, even in the absence of androgens. Understanding these mechanisms is essential for developing more effective treatment strategies for CRPC.

Clinical and molecular epidemiology of malignant salivary gland tumors

Salivary gland carcinomas are a rare and heterogeneous group of malignant tumors, accounting for 3-6% of all malignant tumors in the head and neck region. The 1-, 3- and 5-year survival rates are 83%, 69% and 63% respectively. Due to new molecular pathological and genetic findings, new entities are constantly being defined as part of the recurring WHO classification of salivary gland carcinomas, so that the incidence rates of the entities are subject to constant change. The only certain risk factor for the development of salivary gland carcinomas is ionizing radiation. In addition, large tumors, cervical lymph node involvement and perineural sheath involvement significantly worsen the prognosis. Today, molecular pathology is coming to the fore, with which potential targets have been identified that can offer prognosis-improving treatment options, particularly in recurrent or distant metastatic stages. Entity-specific tyrosine kinase inhibitors such as axitinib in adenoid cystic carcinoma or larotrectinib in secretory carcinoma and cross-entity therapies such as HER2 inhibition and androgen deprivation can prolong median and progression-free survival with a favorable side effect profile.

Comparison of abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer: A multicenter study.

We aimed to assess the differential efficacy and safety of androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, and apalutamide, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a real-world practice setting. We retrospectively reviewed the records of consequent 668 patients with mHSPC treated with ARPI plus androgen deprivation therapy between September 2015 and December 2023. Based on the LATITUDE criteria, the comparison among abiraterone, enzalutamide, and apalutamide was exclusively conducted in high-risk patients. Prostate-specific antigen (PSA) responses such as the achievement of 95% and 99% PSA decline, overall survival (OS), cancer-specific survival (CSS), time to castration-resistant prostate cancer (CRPC), and the incidence of adverse events (AEs) were compared. All two-group comparisons relied on propensity score matching (PSM) to minimize the effect on possible confounders. In total, 297 patients with high-risk mHSPC treated with abiraterone, 127 with enzalutamide, and 142 with apalutamide were compared. There were no differences in time to CRPC (p = 0.13), OS (p = 0.7), and CSS (p = 0.5) among the three ARPIs. No differences were observed in the achievement rates for 95% PSA decline at 3 months among the three ARPIs, while abiraterone was significantly better in 99% PSA decline achievement compared to apalutamide (72% vs. 57%, p = 0.003). The aforementioned oncologic outcomes were sustained even when performing PSM analyzes. Although skin rash for APA (34%) was the highest incidence of AEs, there were no differences in the rates of severe AEs across the three ARPIs. Enzalutamide resulted in the lowest treatment discontinuation rates (10%) other than disease progression compared to the other regimens. Abiraterone, enzalutamide, and apalutamide have comparable oncologic outcomes in terms of OS, CSS, and time to CRPC in patients with high-risk mHSPC. Our data on differential treatment discontinuation rates, PSA response, and AE profiles can help guide clinical decision-making.

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies.

Currently, no biomarkers are available to identify resistance to androgen-deprivation therapies (ADT) in men with hormone-naive prostate cancer. Since 5-hydroxymethylcytosines (5hmC) in gene body are associated with gene activation, in this study, we evaluated whether 5hmC signatures in cell-free DNA (cfDNA) predicts early resistance to ADT. We collected a total of 139 serial plasma samples from 55 prostate cancer patients receiving ADT at three time points including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). To quantify 5hmC abundance across the genome, we used selective chemical labeling sequencing and mapped sequence reads to individual genes. Differential methylation analysis in baseline samples identified significant 5hmC difference in 1,642 of 23,433 genes between patients with and without progression (false discovery rate, FDR<0.1). Patients with disease progression showed significant 5hmC enrichments in multiple hallmark gene sets with androgen responses as top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients featuring a significant 5hmC hypermethylation in the gene sets involving AR , FOXA1 and GRHL2 . To quantify overall activities of these gene sets, we developed a gene set activity scoring algorithm and observed significant association of high activity scores with poor progression-free survival (P<0.05). Longitudinal analysis showed that the high activity scores were significantly reduced after 3-months of initiating ADT (P<0.0001) but returned to higher levels when the disease was progressed (P<0.05). This study demonstrates that 5hmC-based activity scores from gene sets involved in AR , FOXA1 and GRHL2 may be used as biomarkers to determine early treatment resistance, monitor disease progression, and potentially identify patients who would benefit from upfront treatment intensification.

Androgen deprivation therapy, neoadjuvant androgen deprivation therapy, and adjuvant androgen deprivation therapy in patients with locally advanced prostate cancer: a multi-center real-world retrospective study.

Determining the potential benefit of neoadjuvant androgen deprivation therapy (ADT) and adjuvant ADT in patients with locally advanced prostate cancer (LAPC) undergoing complete resection. 139 patients diagnosed with cT3-4, or cN+ LAPC in Xiangya Hospital and The First Affiliated Hospital of University of South China from 2010 to 2021 were collected. Cancer-specific survival (CSS) and overall survival (OS) of patients were assessed using Kaplan-Meier and Cox proportional risk analysis. We also analyzed the functional outcomes of two subgroups of patients who underwent radical prostatectomy (RP). Of the 182 patients with cT3-4, or cN+ LAPC, 139 patients (76.4%) were enrolled in the study with a 5-year survival rate of 82.3%. 45 patients (32.4%) received ADT alone, 46 patients (33.1%) received neoadjuvant ADT before surgery, and the remaining 48 patients (34.5%) received surgery with adjuvant ADT. Neoadjuvant ADT before surgery and surgery with adjuvant ADT were associated with significantly improved survival compared with ADT alone. Multivariate Cox models showed that neoadjuvant ADT before surgery (hazard ratio [HR], 0.29; 95% CI 0.13-0.92) or surgery with adjuvant ADT (HR, 0.26; 95% CI 0.16-0.78) was associated with improved CSS compared with ADT alone. Regional lymph node metastasis, positive lymphovascular invasion, and Gleason score 9 + were independent predictors of LAPC CSS and OS. More patients in the neoadjuvant ADT before surgery group achieved final continence status within 12 months after surgery (93.48% v 77.08%). CSS and OS were significantly prolonged in cT3-4, or cN+ LAPC patients who received neoadjuvant ADT before surgery and surgery with adjuvant ADT compared to ADT alone.

Iodine-125 low-dose rate prostate brachytherapy.

Robotic-assisted laparoscopic radical prostatectomy and intensity-modulated radiation therapy are the most common radical treatments for localized prostate cancer, and brachytherapy (BT) also plays a role in this field. Iodine-125 (I-125) low-dose rate (LDR) prostate BT is an established treatment. However, it remains controversial. Specifically, there are a variety of issues, such as indications for combined treatment with external beam radiotherapy and androgen deprivation therapy, prostate-specific antigen follow-up, the significance of postimplant biopsy, the usefulness of salvage BT and focal therapy, reduction of toxicities, and bladder cancer after BT. In this review, we summarize the recent developments in I-125 LDR BT.

Enzalutamide in metastatic hormone-sensitive prostate cancer: A plain language summary of the ARCHES and ENZAMET follow-up studies.

This summary includes information from the ARCHES and ENZAMET follow-up studies. Both studies looked at enzalutamide treatment for people with metastatic hormone-sensitive prostate cancer (known as mHSPC). In ARCHES, researchers compared the medications enzalutamide+androgen deprivation therapy (known as ADT) with placebo+ADT. In ENZAMET, researchers compared enzalutamide+ADT with standard treatment+ADT. Some people in ENZAMET also took enzalutamide with docetaxel (a chemotherapy treatment). In both studies, researchers wanted to find out if enzalutamide helps people with mHSPC live longer. In both studies, researchers found that people with mHSPC who took enzalutamide lived longer than people who did not. People who took enzalutamide also lived longer without their cancer getting worse. The results were mostly similar in groups of people dependingon when and where their cancer was found. Researchers did not find any new safety concerns. People with mHSPC may benefit from long-term treatment with enzalutamide+ADT. They may also benefit from taking enzalutamide with other treatments, like docetaxel. It may be better for people with mHSPC to have enzalutamide treatment before their cancer gets worse, rather than waiting. These people and their doctors should carefully consider the benefits and risks of each treatment to make a joint decision for treating mHSPC.Clinical Trial Registration: NCT02677896 (ARCHES), NCT02446405 (ENZAMET) (ClinicalTrials.gov).

Preliminary Efficacy, Tolerability, and Safety Analysis of Darolutamide for Metastatic Castration-Resistant Prostate Cancer: A Single-Center, Open-Label Study

Introduction: Darolutamide is a structurally unique second-generation androgen receptor antagonist that has been approved for indications in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). The aim was to assess the efficacy and safety of Darolutamide for mCRPC. Methods: In this single-center, open-label study, patients with previously untreated mCRPC were enrolled and received androgen deprivation therapy (goserelin acetate 3.6 mg every 28 days) and docetaxel (75 mg per square meter of body surface area every 21 days) with Denosumab (120 mg every 28 days) for bone metastases, Darolutamide (300 mg orally twice daily) in the experimental group, and the control group received the corresponding of placebo. Serum PSA changes were detected and recorded, and imaging changes and adverse events (AEs) were evaluated. The primary endpoints were safety, tolerability, and antitumor efficacy, and the second endpoint was radiographic progression-free survival (rPFS). Results: Thirty-seven patients with mCRPC were enrolled. The median time to PSA50 in the Darolutamide group was 1.5 months (95% CI: 0.2619–0.9545), significantly lower than that in the placebo group (3.0 months [95% CI: 1.048–3.818], p = 0.0259). The median time to PSA90 in the experimental group was 4 months (95% CI: 0.3094–1.437), 2 months shorter than that in the placebo group (6.0 months [95% CI: 0.6961–3.232]). With the median follow-up of 6 months, the median decrease in serum PSA was −81.8% (range −60.4 to −99.9%) in the Darolutamide group and −69.4% (range −50.3 to −89.6%) in the placebo group. Tumor-related pain and AEs were not increased, and the median rPFS was not reached. Conclusions: The combination of Darolutamide and docetaxel was well tolerated with more clinically beneficial than docetaxel alone in previously untreated mCRPC. Darolutamide rapidly reduced PSA levels and prolonged rPFS and did not increase the incidence of AEs.

The Hexosamine Biosynthetic Pathway alters the cytoskeleton to modulate cell proliferation and migration in metastatic prostate cancer.

Castration-resistant prostate cancer (CRPC) progresses despite androgen deprivation therapy, as cancer cells adapt to grow without testosterone, becoming more aggressive and prone to metastasis. CRPC biology complicates the development of effective therapies, posing challenges for patient care. Recent gene-expression and metabolomics studies highlight the Hexosamine Biosynthetic Pathway (HBP) as a critical player, with key components like GNPNAT1 and UAP1 being downregulated in metastatic CRPC. GNPNAT1 knockdown has been shown to increase cell proliferation and metastasis in CRPC cell lines, though the mechanisms remain unclear. To investigate the cellular basis of these CRPC phenotypes, we generated a CRISPR-Cas9 knockout model of GNPNAT1 in 22Rv1 CRPC cells, analyzing its impact on metabolomic, glycoproteomic, and transcriptomic profiles of cells. We hypothesize that HBP inhibition disrupts the cytoskeleton, altering mitotic progression and promoting uncontrolled growth. GNPNAT1 KO cells showed reduced levels of cytoskeletal filaments, such as actin and microtubules, leading to cell structure disorganization and chromosomal mis-segregation. GNPNAT1 inhibition also activated PI3K/AKT signaling, promoting proliferation, and impaired cell adhesion by mislocalizing EphB6, enhancing migration via the RhoA pathway and promoting epithelial-to-mesenchymal transition. These findings suggest that HBP plays a critical role in regulating CRPC cell behavior, and targeting this pathway could provide a novel therapeutic approach.

Effects of gender-affirming hormone therapy on lower urinary tract symptoms and sexual function among transgender individuals.

Gender-affirming hormone therapy (GAHT) includes estrogen preparations and androgen inhibitors for transgender women, and testosterone preparations for transgender men. The aim of the study was to investigate possible effects of GAHT on lower urinary tract symptoms (LUTS) and sexual function among transgender individuals. Fifty-one transgender men and 47 transgender women were prospectively recruited. Four validated female questionnaires (Bristol Female Lower Urinary Tract Symptoms [BFLUTS] questionnaire, the Medical, Epidemiologic, and Social aspects of Aging [MESA] questionnaire, Urgency, the Severity and Impact Questionnaire [USIQ], and the Female Sexual Function Index [FSFI]) and two validated male questionnaires (International Prostate Symptom Score [IPSS], and the International Index of Erectile Function [IIEF]) were used to assess LUTS and sexual function among transgender men and women, respectively, before and during GAHT. Follow-up was performed over a period of 3-12 months. Thirty-four transgender men (mean age 24.4 ± 7.6 years) and 31 transgender women (mean age 29 ± 8.7 years) completed all questionnaires, before and during GAHT. Testosterone treatment was associated with a statistically significant improvement in sexual desire among transgender men, as reflected in the FSFI questionnaire (4.5 ± 1.2 vs. 3.6 ± 1.3, P = 0.002). None of the three LUTS questionnaires showed statistically significant changes during the treatment with testosterone preparations. Estrogen treatment was associated with a statistically significant decrease in erectile function among transgender women, as reflected by the IIEF questionnaire (9.0 ± 7.2 vs. 14.1 ± 11.1, P = 0.012). No significant changes were found in LUTS during the treatment with estrogen preparations, except for a slight worsening of nocturia (2.1 ± 1.8 vs. 1.1 ± 1.4, P = 0.009). GAHT was not found to be associated with significant LUTS in both transgender men and women. Nevertheless, some effects on sexual function were observed, mainly a decrease in erectile function among transgender women and an increase in sexual desire among transgender men.

Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer.

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.

Metformin in Overcoming Enzalutamide Resistance in Castration-Resistant Prostate Cancer.

Androgen deprivation is the standard treatment for prostate cancer (PCa) patients. However, the disease eventually progresses as castration-resistant PCa (CRPC). Enzalutamide, an AR inhibitor, is a typical drug to treating CRPC and due to continuous reliance on the drug, can lead to Enzalutamide-resistance (ENZ-r). This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential anti-tumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of ENZ-r CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in ENZ-r CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro Following these results, we sought to explore how combination treatment effected mitochondrial fitness utilizing mitochondrial stress test analysis and mitochondrial membrane potential (MMP) shifts due to metformin's action in inhibiting Complex I of oxidative phosphorylation. We employed 2 different strategies of in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of Ras/MAPK signaling following combination treatment. Significance Statement Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. We showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.