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Archives of Gynecology and Obstetrics Oct 2023The aim of this NMA is to comprehensively analyze evidence of oral GnRH antagonist in the treatment of moderate-to-severe endometriosis-associated pain. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The aim of this NMA is to comprehensively analyze evidence of oral GnRH antagonist in the treatment of moderate-to-severe endometriosis-associated pain.
METHODS
Literature searching was performed to select eligible studies published prior to April 2022 in PubMed, Cochrane, Embase and Web of Science. Randomized controlled trials involving patients who suffered from moderate-to-severe endometriosis-associated pain and treated with oral nonpeptide GnRH antagonists or placebo were included.
RESULTS
Elagolix 400 mg and ASP1707 15 mg were most efficient in reducing pelvic pain, dysmenorrhea and dyspareunia. Relugolix 40 mg was best in reducing the analgesics use. The rates of any TEAEs and TEAEs-related discontinuation were highest in relugolix 40 mg and elagolix 250 mg, respectively, while rates of hot flush and headache were highest in relugolix 40 mg and elagolix 150 mg. Significantly decreased spinal BMD was observed in elagolix 250 mg.
CONCLUSION
Oral GnRH antagonists were effective in endometriosis-associated pain in 12w, and most of the efficiency and safety outcomes were expressed in a dose-dependent manner, but linzagolix 75 mg was an exception.
Topics: Female; Humans; Endometriosis; Network Meta-Analysis; Gonadotropin-Releasing Hormone; Hormone Antagonists; Pelvic Pain
PubMed: 36656435
DOI: 10.1007/s00404-022-06862-0 -
Cancer Gene Therapy Oct 2023Androgen deprivation therapy (ADT) is the standard care for advanced prostate cancer (PCa) patients. Unfortunately, although tumors respond well initially, they enter...
Androgen deprivation therapy (ADT) is the standard care for advanced prostate cancer (PCa) patients. Unfortunately, although tumors respond well initially, they enter dormancy and eventually progress to fatal/incurable castration-resistant prostate cancer (CRPC). B7-H3 is a promising new target for PCa immunotherapy. CD276 (B7-H3) gene has a presumptive androgen receptor (AR) binding site, suggesting potential AR regulation. However, the relationship between B7-H3 and AR is controversial. Meanwhile, the expression pattern of B7-H3 following ADT and during CRPC progression is largely unknown, but critically important for identifying patients and determining the optimal timing of B7-H3 targeting immunotherapy. In this study, we performed a longitudinal study using our unique PCa patient-derived xenograft (PDX) models and assessed B7-H3 expression during post-ADT disease progression. We further validated our findings at the clinical level in PCa patient samples. We found that B7-H3 expression was negatively regulated by AR during the early phase of ADT treatment, but positively associated with PCa proliferation during the remainder of disease progression. Our findings suggest its use as a biomarker for diagnosis, prognosis, and ADT treatment response, and the potential of combining ADT and B7-H3 targeting immunotherapy for hormone-naïve PCa treatment to prevent fatal CRPC relapse.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Longitudinal Studies; Disease Progression; Neoplasm Recurrence, Local; Receptors, Androgen; Transcription Factors; Hormones; B7 Antigens
PubMed: 37452083
DOI: 10.1038/s41417-023-00644-9 -
Journal of Translational Medicine Nov 2023Prostate cancer (PCA) is the fifth leading cause of cancer-related deaths worldwide, with limited treatment options in the advanced stages. The immunosuppressive tumor...
BACKGROUND
Prostate cancer (PCA) is the fifth leading cause of cancer-related deaths worldwide, with limited treatment options in the advanced stages. The immunosuppressive tumor microenvironment (TME) of PCA results in lower sensitivity to immunotherapy. Although molecular subtyping is expected to offer important clues for precision treatment of PCA, there is currently a shortage of dependable and effective molecular typing methods available for clinical practice. Therefore, we aim to propose a novel stemness-based classification approach to guide personalized clinical treatments, including immunotherapy.
METHODS
An integrative multi-omics analysis of PCA was performed to evaluate stemness-level heterogeneities. Unsupervised hierarchical clustering was used to classify PCAs based on stemness signature genes. To make stemness-based patient classification more clinically applicable, a stemness subtype predictor was jointly developed by using four PCA datasets and 76 machine learning algorithms.
RESULTS
We identified stemness signatures of PCA comprising 18 signaling pathways, by which we classified PCA samples into three stemness subtypes via unsupervised hierarchical clustering: low stemness (LS), medium stemness (MS), and high stemness (HS) subtypes. HS patients are sensitive to androgen deprivation therapy, taxanes, and immunotherapy and have the highest stemness, malignancy, tumor mutation load (TMB) levels, worst prognosis, and immunosuppression. LS patients are sensitive to platinum-based chemotherapy but resistant to immunotherapy and have the lowest stemness, malignancy, and TMB levels, best prognosis, and the highest immune infiltration. MS patients represent an intermediate status of stemness, malignancy, and TMB levels with a moderate prognosis. We further demonstrated that these three stemness subtypes are conserved across pan-tumor. Additionally, the 9-gene stemness subtype predictor we developed has a comparable capability to 18 signaling pathways to make tumor diagnosis and to predict tumor recurrence, metastasis, progression, prognosis, and efficacy of different treatments.
CONCLUSIONS
The three stemness subtypes we identified have the potential to be a powerful tool for clinical tumor molecular classification in PCA and pan-cancer, and to guide the selection of immunotherapy or other sensitive treatments for tumor patients.
Topics: Male; Humans; Prostatic Neoplasms; Prognosis; Androgen Antagonists; Multiomics; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 37936202
DOI: 10.1186/s12967-023-04683-6 -
International Journal of Molecular... Jul 2023Prostate cancer is one of the most common malignant diseases in men, and it contributes significantly to the increased mortality rate in men worldwide. This study aimed... (Review)
Review
Prostate cancer is one of the most common malignant diseases in men, and it contributes significantly to the increased mortality rate in men worldwide. This study aimed to review the roles of p300 and TMPRSS2 (transmembrane protease, serine 2) in the AR (androgen receptor) pathway as they are closely related to the development and progression of prostate cancer. This paper represents a library-based study conducted by selecting the most suitable, up-to-date scientific published articles from online journals. We focused on articles that use similar techniques, particularly those that use prostate cancer cell lines and immunohistochemical staining to study the molecular impact of p300 and TMPRSS2 in prostate cancer specimens. The fusion is considered relevant to prostate cancer, but its association with the development and progression as well as its clinical significance have not been fully elucidated. On the other hand, high p300 levels in prostate cancer biopsies predict larger tumor volumes, extraprostatic extension of disease, and seminal vesicle involvement at prostatectomy, and may be associated with prostate cancer progression after surgery. The inhibition of p300 has been shown to reduce the proliferation of prostate cancer cells with (E26 transformation-specific) fusions, and combining p300 inhibitors with other targeted therapies may increase their efficacy. Overall, the interplay between the p300 and TMPRSS2 pathways is an active area of research.
Topics: Humans; Male; Biopsy; Oncogene Proteins, Fusion; Prostate; Prostatic Neoplasms; Serine Endopeptidases; Transcriptional Regulator ERG; p300-CBP Transcription Factors
PubMed: 37511059
DOI: 10.3390/ijms241411299 -
Nature Communications Feb 2024Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT...
Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.
Topics: Male; Humans; Mice; Animals; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; beta Catenin; Active Transport, Cell Nucleus; Wnt Signaling Pathway; Ribosomal Proteins; Receptors, Androgen; Cell Line, Tumor; Hepatocyte Growth Factor
PubMed: 38336745
DOI: 10.1038/s41467-024-45489-4 -
The Oncologist Mar 2024In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5%...
BACKGROUND
In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS.
PATIENTS AND METHODS
Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety.
RESULTS
In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%).
CONCLUSION
In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic
PubMed: 37812679
DOI: 10.1093/oncolo/oyad254 -
EBioMedicine Sep 2023Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events...
BACKGROUND
Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes.
METHODS
Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2.
FINDINGS
At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months).
INTERPRETATION
These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials.
FUNDING
Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
Topics: Humans; Male; Androgen Receptor Antagonists; Biomarkers, Tumor; Cell-Free Nucleic Acids; Genomics; Phenotype; Phosphatidylinositol 3-Kinases; Prognosis; Prostatic Neoplasms, Castration-Resistant
PubMed: 37549632
DOI: 10.1016/j.ebiom.2023.104738 -
Nucleic Acids Research Jan 2024Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies,...
Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300's enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.
Topics: Humans; Male; Androgen Antagonists; Cell Line, Tumor; Chromatin; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha; Prostatic Neoplasms; Receptors, Androgen; Receptors, Glucocorticoid
PubMed: 38015476
DOI: 10.1093/nar/gkad1126 -
Trials Sep 2023Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide....
SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs.
METHODS
In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO.
DISCUSSION
The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention.
TRIAL REGISTRATION
EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .
Topics: Adolescent; Female; Humans; Carotid Intima-Media Thickness; Clinical Trials, Phase II as Topic; Insulin; Life Style; Metformin; Multicenter Studies as Topic; Pioglitazone; Polycystic Ovary Syndrome; Quality of Life; Randomized Controlled Trials as Topic; Spironolactone; Young Adult
PubMed: 37715279
DOI: 10.1186/s13063-023-07593-6 -
Current Oncology (Toronto, Ont.) Feb 2024Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of... (Review)
Review
Prostate cancer accounts for a significant proportion of cancer diagnoses in Canadian men. Over the past decade, the therapeutic landscape for the management of metastatic prostate cancer has undergone rapid changes. Novel strategies use hormonal agents, chemotherapy, homologous recombination repair inhibitors, and radioligand therapy or combination strategies in addition to androgen deprivation therapy. In this review, we summarize the available data addressing key therapeutic areas along the disease continuum and focus on practical aspects for general practitioners in oncology managing patients with metastatic prostate cancer.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; General Practitioners; Poly(ADP-ribose) Polymerase Inhibitors; Canada
PubMed: 38392072
DOI: 10.3390/curroncol31020078