ABSTRACT
Prostate cancers may reactivate a latent embryonic program called the epithelial-mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/ß-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.
Subject(s)
Biomarkers, Tumor/genetics , Epithelial-Mesenchymal Transition/genetics , Neoplastic Stem Cells/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Signal Transduction/genetics , Animals , Humans , Male , Precision Medicine/methodsABSTRACT
Conjugated oestrogen is one of the more affordable secondary hormonal options available for castrate-resistant prostate cancer (CRPC) in Jamaica. The present study was conducted to examine the disease response in Jamaican men with CRPC treated with conjugated oestrogen. This study retrospectively reviewed the medical notes of patients who attended the urologic clinic of the University Hospital of the West Indies from 1 January 2009 to 31 December 2013 and a private urology clinic from 2 November 2005 to 3 June 2015 to identify patients diagnosed with CRPC treated with conjugated oestrogen (Premarin ®) as secondary therapy. The primary endpoint of favourable response, using the Prostate Cancer Clinical Trials Working Group 2 criteria is a decline of ≥50% in serum prostate-specific antigen (PSA) concentrations from baseline after treatment. The proportion of patients responding by the first 3-month follow-up visit and the maximal PSA declined over the 24 months of follow-up which were recorded. Thirty-two patients diagnosed with CRPC and treated with conjugated oestrogen were identified. All patients were prescribed 5.0 mg (2.5 mg tablets, twice daily) orally, as well as low dose aspirin. Favourable response was observed in 14 (43.8%) patients; however, eight other patients showed a decline in serum PSA concentration of <50%. There were no reported adverse effects. Conjugated oestrogen produced a PSA decline in Jamaican CRPC patients of this study and may therefore be a useful option for secondary therapy of CRPC. Further assessment is needed.
ABSTRACT
Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone-leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.