Unlabelled: We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study. We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC). At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.
Implications: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.
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http://dx.doi.org/10.1158/1541-7786.MCR-22-0099 | DOI Listing |
J Med Internet Res
January 2025
Cancer Rehabilitation and Survivorship, Department of Supportive Care, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Background: Virtual follow-up (VFU) has the potential to enhance cancer survivorship care. However, a greater understanding is needed of how VFU can be optimized.
Objective: This study aims to examine how, for whom, and in what contexts VFU works for cancer survivorship care.
PLoS One
January 2025
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.
Epithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prior studies of primary prostate cancer tumour genetics revealed extensive inter and intra-patient genomic tumour heterogeneity. Recent advances in machine learning have enabled the inference of ground-truth genomic single-nucleotide and copy number variant status from transcript data.
View Article and Find Full Text PDFEndocr Relat Cancer
January 2025
S Dehm, Masonic Cancer Center, University of Minnesota, Minneapolis, United States.
Treatment for castration-resistant prostate cancer (CRPC) primarily involves the suppression of androgen receptor (AR) activity using androgen receptor signaling inhibitors (ARSIs). While ARSIs have extended patient survival, resistance inevitably develops. Mechanisms of resistance include genomic aberrations at the AR locus that reactivate AR signaling, or lineage plasticity that drives emergence of AR-independent phenotypes.
View Article and Find Full Text PDFJAMA Netw Open
January 2025
Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles.
Importance: The phase 3 randomized EMBARK trial evaluated enzalutamide with or without leuprolide in high-risk nonmetastatic hormone-sensitive prostate cancer. Eligibility relied on conventional imaging, which underdetects metastatic disease compared with prostate-specific membrane antigen-positron emission tomography (PSMA-PET).
Objective: To describe the staging information obtained by PSMA-PET/computed tomography (PSMA-PET/CT) in a patient cohort eligible for the EMBARK trial.
Int Urol Nephrol
January 2025
Faculty of Medical Sciences, Pharmacology and Toxicology Department, University of Kragujevac, Kragujevac, Serbia.
Purposes: Intermediate-risk prostate cancer (IR PCa) is the most common risk group for localized prostate cancer. This study aimed to develop a machine learning (ML) model that utilizes biopsy predictors to estimate the probability of IR PCa and assess its performance compared to the traditional clinical model.
Methods: Between January 2017 and December 2022, patients with prostate-specific antigen (PSA) values of ≤ 20 ng/mL underwent transrectal ultrasonography-guided prostate biopsies.
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