Possible clinical implication of serum testosterone surge caused by the GnRH antagonist degarelix.
Gaku AraiKojiro NishioRyo SatoMakoto KawaguchiKeisuke SuzukiToshiyuki IwahataYuko SadaokaShigeyuki OtaMasashi IijimaTakeshi ShinYoshio AshizawaYoshitomo KoboriHiroshi YagiShigehiro SohHiroshi Okada
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e16097 Background: Degarelix directly blocks GnRH receptors, therefore, it is believed to produce a rapid decline of serum testosterone level without an initial surge in leutenizing hormone (LH), follicule stimulating hormone (FSH) and testosterone(T) seen in LHRH agonists. However, hormonal change caused by Degarelix in ultra-acute phase is unknown. We investigated the change of serum levels of LH, FSH and testosterone within 24hours of administration of Degarelix. Methods: Eleven patients (median age 74 years old; range 63-74), with a histologic diagnosis of advanced prostate cancer and without pretreatment by androgen deprivation therapy, were involved. Serum levels of LH, FSH and T were measured at 0, 1, 3, 6, 9, 12, 24 hours and1 month after injection of Degarelix. Serum prostate-specific antigen (PSA) level was also measured at baseline and 1 month after treatment. Results: The median serum PSA level before treatment was 378ng/ml (15.9-7187). The median baseline serum levels of LH, FSH and T were 7.6mIU/ml (2.9-17), 10.6mIU/ml (2.4-32) and 390ng/dL (206-697), respectively. Those at 24hr were 0.7mIU/ml (0.01-2), 6.6mIU/ml (1.4-18.6) and 50ng/ml (8-95). Although, serum levels of LH and T declined rapidly, serum levels of FSH declined more slowly. In 5 patients, serum levels of T at 24hr were below the castration level (<50ng/dL). T surge (an elevation of serum level of T within first 3hr) was observed in 6 patients. In 9 patients, hormonal levels at 1 month after treatment were available. In 7 of 9 patients, serum levels of T were below the castration level. Four patients showed T surge and 5 did not show this phenomenon. In four of 5 patients without T surge, serum levels of PSA declined to 96% in average at 1 month. In contrast, only one of 4 patients with T surge showed 92% reduction of serum levels of PSA, in the rest of 3 patients PSA reduction was only 67% in average. Conclusions: Degarelix suppresses serum levels of and Testosterone rapidly. Testosterone surge could be a possible predictor of effectiveness of Degarelix on prostate cancer.Keywords:
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Prostate cancer is a malignancy commonly occuring in male genitourinary system.Androgen receptor promotes gene transcription in prostate cell growth and carcinogenesis of prostate cancer,which makes it to become an important target in prostate cancer treatment possibly.Prostate cancer may be deteriorated into be castration-resistant prostate cancer easily after androgen deprivation therapy,so it is popular to seek the effective androgen receptor antagonists for treating of castration-resistant prostate cancer.This review focuses on the action mechanism and the development of androgen receptor antagonists for the treatment of prostate cancer.
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Abstract Carcinoma of the prostate is the most common cancer in men. Treatment of aggressive prostate cancer involves a regiment of radical prostectomy, radiation therapy, chemotherapy and hormonal therapy. Despite significant improvements in the last decade, the treatment of prostate cancer remains unsatisfactory, because a significant fraction of prostate cancers develop resistance to multiple treatments and become incurable. This prompts an urgent need to investigate the molecular mechanisms underlying the evolution of therapy-induced resistance of prostate cancer either in the form of castration-resistant prostate cancer (CRPC) or transdifferentiated neuroendocrine prostate cancer (NEPC). By analyzing micro-RNA expression profiles in a set of patient-derived prostate cancer xenograft tumor lines, we identified miR-100-5p as one of the key molecular components in the initiation and evolution of androgen ablation therapy resistance in prostate cancer. In vitro results showed that miR-100-5p is required for hormone-independent survival and proliferation of prostate cancer cells post androgen ablation. In Silico target predictions revealed that miR-100-5p target genes are involved in key aspects of cancer progression, and are associated with clinical outcome. Our results suggest that mir-100-5p is a possible therapeutic target involved in prostate cancer progression and relapse post androgen ablation therapy.
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Serum prostate specific antigen is a highly specific test for diseases of the prostate gland but it is not specific for prostate cancer, which can lead to unnecessary biopsies. In an effort to find a more specific test, a new testing method for detecting prostate cancer based on deglycosylation of cell surface proteins and subsequent antibody formation in patients with prostate cancer was evaluated. In addition, antibody generation against the peptide fragments chosen to represent the cell surface proteins was determined to be cancer associated, cancer specific or not related to prostate cancer.Antibody titers to 67 unique peptide sequences representing 41 cell surface proteins were determined in 25 men with known prostate cancer (cancer group) and 34 men without prostate cancer (control group). The titers of the control and cancer groups were compared for statistical significance. Additionally, each peptide was identified as being cancer specific, cancer associated or not related to prostate cancer based on whether patients, controls, both or neither had elevated antibody titers.Of the 67 peptides tested 3 demonstrated statistical significance between the control and cancer group titers. Using these 3 informative peptides, 11 of the 25 men known to have prostate cancer had positive results (sensitivity 44%), while 2 of the 34 control patients had positive results (specificity 94%). Of the peptides with significantly different titers in patients and controls 2 of the 19 cell surface proteins known to be present in prostate cancer were represented. No peptides were found to generate antibodies only in patients with cancer (cancer specific), while 3 were cancer associated (increased in cancer and controls).A new approach to testing for prostate cancer, although lacking in sensitivity, appears to be highly specific. The high specificity of this test suggests that when combined with a highly sensitive test, such as prostate specific antigen, screening could be significantly improved.
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Androgen deprivation therapy has been the standard treatment for the patients with advanced prostate cancer. Androgen deprivation therapy initially suppresses the growth of prostate cancer. However, most patients eventually progress to castration-resistant prostate cancer. Novel drugs, including enzalutamide and abiraterone acetate, are recently able to be used for the patients with castration-resistant prostate cancer. Even so, the therapeutic options for castration-resistant prostate cancer are not enough. Interestingly, androgen receptor degradation enhancer ASC-J9 is reported to degrade the androgen receptor, resulting in the suppression of the growth in castration-resistant prostate cancer cells. In this chapter, ASC-J9 for prostate cancer is reviewed.
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Prostate cancer is one of the most common and socially significant cancers among men. The aim of this study was to identify significant changes in the expression of exosomal miRNAs associated with an increase in the level of prostate specific antigen in castration-resistant prostate cancer during therapy and to evaluate them as potential prognostic markers for this category of disease. High-throughput miRNA sequencing was performed on 49 blood plasma samples taken from 11 Russian patients with castration-resistant cancer during therapy. Bioinformatic analysis of the obtained miRNA-seq data was carried out. Additionally, miRNA-seq data from the PRJNA562276 project were analyzed to identify exosomal miRNAs associated with castration-resistant prostate cancer. We found 34 differentially expressed miRNAs associated with the progression of castration-resistant prostate cancer during therapy in Russian patients. It was also shown that hsa-miRNA-148a-3p expression can serve as a potential prognostic marker. We found the exosomal miRNA expression signature associated with castration-resistant prostate cancer progression, in particular on the Russian patient cohort. Many of these miRNAs are well-known players in either oncogenic transformation or tumor suppression. Further experimental studies with extended sampling are required to validate these results.
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Androgen deprivation therapy can effectively suppress the progression of prostate cancer, but accumulating evidence for the relationship of testosterone with prostate cancer challenges the conventional wisdom. High levels of testosterone are not risk factors for prostate cancer, nor promote its development. On the contrary, a low testosterone level indicates a worse pathological stage. So far there has been no strong evidence to prove the role of testosterone in the occurrence and progression of prostate cancer. Therefore, the relationship between testosterone and prostate cancer is quite complicated and deserves further investigation.
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Recurrence of localized prostate cancer following treatment can lead to lethal metastatic castration-resistant prostate cancer. Although numerous studies aimed at developing biomarkers for predicting recurrence of localized prostate cancer are promising, they have not yet led to useful applications. Dysregulation of exportins (XPOs, nucleocytoplasmic transporters) associated with subcellular mislocalization of proteins has been reported for various human cancers. However, most of the XPOs have not been studied in prostate cancer. In this study, we are the first to examine whether changes in expression of XPOs could be used as potential biomarkers for recurrence of localized prostate cancer. Using the oncomine database, gene expressions of 7 known XPOs by 1128 patient samples, obtained from 16 independent prostate cancer patient cohorts, were analyzed. Relatively highly elevated expression of XPO6 (compared to prostate cancer tissue) was found to be significantly associated with poor patient prognosis, in particular, with rapid recurrence in a clinical low risk group. As such, expression of XPO6 may be a potential prognostic biomarker for predicting prostate cancer recurrence.
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