The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. gene alterations were more common in nonresponders, although this did not reach statistical significance ( = 0.055). gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.
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http://dx.doi.org/10.1073/pnas.1922207117 | DOI Listing |
Biochem Genet
January 2025
Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
This study aimed to identify shared gene expression related to circadian rhythm disruption in polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) to discover common diagnostic biomarkers. Visceral fat RNA samples were collected from 12 PCOS and 14 non-PCOS patients, a sample size representing the clinical situation and sufficient to capture PCOS gene expression profiles. Along with liver transcriptome profiles from NAFLD patients, these data were analyzed to identify crosstalk circadian rhythm-related genes (CRRGs) between the diseases.
View Article and Find Full Text PDFGenome Med
January 2025
Department of Systems Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, 10032, USA.
Background: Despite extensive analysis, the dynamic changes in prostate epithelial cell states during tissue homeostasis as well as tumor initiation and progression have been poorly characterized. However, recent advances in single-cell RNA-sequencing (scRNA-seq) technology have greatly facilitated studies of cell states and plasticity in tissue maintenance and cancer, including in the prostate.
Methods: We have performed meta-analyses of new and previously published scRNA-seq datasets for mouse and human prostate tissues to identify and compare cell populations across datasets in a uniform manner.
Eur J Nucl Med Mol Imaging
January 2025
Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
Purpose: To report real-world clinical experience with [Lu]Lu-PSMA-I&T targeted radionuclide therapy (TRT) in patients with metastatic castration-resistant prostate cancer (mCRPC) in a single tertiary referral university hospital.
Methods: Patients with mCRPC who were treated with [Lu]Lu-PSMA-I&T TRT as standard of care between February 2022 and August 2023 were included in this retrospective study. Patients were treated with a maximum of six cycles with a fixed activity of 7.
Eur Urol Oncol
January 2025
Cancer Heterogeneity Plasticity and Resistance to Therapies (CANTHER) Research Group, CHU Lille, Institut Pasteur de Lille, and University of Lille, Lille, France; Department of Urology, Hospital Claude Huriez, CHU Lille, Lille, France. Electronic address:
Background And Objective: It has been shown that androgen receptor pathway inhibitor (ARPIs) treatment for metastatic castration-resistant prostate cancer (mCRPC) improves overall survival rates, but ARPIs appear to be associated with a higher frequency of treatment-related neuroendocrine prostate cancer (t-NEPC). Our aim was to quantify the proportion of prostate adenocarcinoma cases that transition to t-NEPC following ARPI therapy.
Methods: We conducted a comprehensive search of the literature on t-NEPC using databases including MEDLINE and Scopus.
Rapid Commun Mass Spectrom
April 2025
Camel Forensic Laboratory, Central Veterinary Research Laboratory, Dubai, UAE.
Rationale: LGD-4033, a selective androgen receptor modulator (SARM), is recognized for promoting muscle growth and enhancing athletic performance. Its potent anabolic effects have led to its prohibition in both human and animal sports. Although initial in vitro studies have offered insights into its metabolism, an in-depth in vivo analysis is necessary to fully understand its metabolic pathways.
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