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雄激素受体是前列腺癌发生发展的重要因素。雄激素去势疗法是目前治疗前列腺癌的标准疗法,在早期可以有效的抑制肿瘤生长。但2~3年内,肿瘤会复发或进展,形成去势抵抗性前列腺癌。目前关于雄激素去势疗法治疗后去势抵抗性前列腺癌发生发展机制研究的文献较多(其中包括类固醇激素代谢的变化、雄激素受体基因的扩增或过表达、雄激素受体辅助调节因子、雄激素受体剪接变异体、生长因子和/或细胞因子、雄激素受体突变等等机制),但还没有对具体机制完全了解并形成共识。目前普遍认为在去势抵抗性前列腺癌中,雄激素和雄激素受体在其发生发展中起到了关键的作用。本文就雄激素受体在前列腺癌进展为去势抵抗性前列腺癌的机制中的作用加以综述。 相似文献
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目的:探讨长链非编码RNA PlncRNA-1在雄激素非依赖的前列腺癌细胞中的作用。方法:选取雄激素依赖的前列腺癌细胞系LNCaP及雄激素非依赖的前列腺癌细胞系C4-2,应用实时定量PCR技术检测两种细胞系中PlncRNA-1的表达差异。RNA干涉技术沉默PRNCR1的表达,检测AR表达变化。流式细胞术检测细胞周期及凋亡的变化。MTT实验检测对细胞增殖的影响。细胞侵袭实验检测细胞侵袭能力的变化。结果:PlncRNA-1在雄激素非依赖的细胞系C4-2中高表达。沉默其表达可以明显降低前列腺癌细胞中AR的表达,抑制前列腺癌细胞的细胞周期、增殖及细胞的侵袭能力,并促进细胞的凋亡。结论:PlncRNA-1在前列腺癌细胞中通过调节AR,影响细胞的增殖、凋亡及细胞的侵袭能力,PlncRNA-1可能在前列腺癌CRPC进展中发挥着重要作用。 相似文献
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我国前列腺癌的发病率在不断上升,去势治疗可使约80%的晚期前列腺癌患者症状得到一定的好转,但效果维持平均只有12~16个月,此后前列腺癌继续生长、恶化,发展为雄激素抵抗型前列腺癌(HRPC)。出现顽固性骨痛、血尿、贫血等多种并发症,严重影响患者的生活质量。1998年8月~2002年6月,作者应用核素氯化锶(^89Sr)、二膦酸盐(洛曲)、外照射、止痛剂综合治疗18例雄激素抵抗型前列腺癌患者,报道如下。 相似文献
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目的:观察甲羟孕酮对于去势抵抗型前列腺癌(CRPC)的疗效及毒副反应。方法:观察62例 CRPC患者口服甲羟孕酮后,对比口服药物前后 PSA、生活质量 KPS 评分、血红蛋白、营养状况的变化,评价药物毒副反应。结果:62例患者经过口服甲羟孕酮后,PSA 下降的有效率为11.3%、稳定率达24.2%。KPS 评分、血红蛋白较前明显改善(P 值均<0.05)。营养状况的改善率为64.5%、稳定率达30.6%。未发现 III -IV 级毒副反应,6例出现轻度低钠血症,5例出现轻度低钾血症,Ⅰ度下肢水肿较治疗前增加4例。结论:甲羟孕酮可延缓部分 CRPC 患者的 PSA 进展,改善晚期肿瘤患者的生活质量,毒副反应小。 相似文献
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摘 要:我国前列腺癌发病率呈逐年上升的趋势。早期前列腺癌有治愈可能,但进展期或转移性前列腺癌无法治愈。近年来,具有肿瘤选择性复制并杀伤肿瘤细胞而对正常细胞毒性较低的溶瘤腺病毒治疗前列腺癌的研究有诸多报道,临床前研究已经显示了其强大的溶瘤效果,临床研究也验证了其抗肿瘤效果和安全性,溶瘤腺病毒单独及联合放化疗治疗去势抵抗性前列腺癌的研究显示了一定的疗效。 相似文献
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雄激素受体(androgen receptor,AR)作为核内转录因子是前列腺癌中最常见的治疗靶标,在去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)中雄激素受体也起到了非常重要的作用。去势抵抗性前列腺癌的发生发展机制是当前的研究热点。表观遗传学的改变在前列腺癌的发展中具有重要作用。甲基化、乙酰化及非编码RNA可以通过对雄激素受体信号通路的调控促进或者抑制前列腺癌的发生发展。本文将近期关于前列腺癌雄激素受体信号通路表观遗传学的调节机制进行综述。 相似文献
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《Expert review of anticancer therapy》2013,13(4):425-432
Prostate cancer (PCa) is the second leading cause of cancer-related death in men. Androgen receptor has a key role in the initiation and progression of PCa. Currently, androgen deprivation therapy is the standard treatment for PCa patients due to its effective suppression of androgen receptor signaling. Even though androgen deprivation therapy shows its initial effectiveness on shrinking tumor size, it eventually fails to cure advanced PCa, which is determined by the occurrence of castration-resistance. In this review, we summarize the widely accepted mechanisms that account for castration-resistant PCa and discuss potential therapeutic targets. 相似文献
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Sven Perner Marcus V. Cronauer Andres Jan Schrader Helmut Klocker Zoran Culig Aria Baniahmad 《Oncotarget》2015,6(34):35542-35555
Prostate Cancer (PCa) is an important age-related disease being the most common cancer malignancy and the second leading cause of cancer mortality in men in Western countries. Initially, PCa progression is androgen receptor (AR)- and androgen-dependent. Eventually advanced PCa reaches the stage of Castration-Resistant Prostate Cancer (CRPC), but remains dependent on AR, which indicates the importance of AR activity also for CRPC. Here, we discuss various pathways that influence the AR activity in CRPC, which indicates an adaptation of the AR signaling in PCa to overcome the treatment of PCa. The adaptation pathways include interferences of the normal regulation of the AR protein level, the expression of AR variants, the crosstalk of the AR with cytokine tyrosine kinases, the Src-Akt-, the MAPK-signaling pathways and AR corepressors. Furthermore, we summarize the current treatment options with regard to the underlying molecular basis of the common adaptation processes of AR signaling that may arise after the treatment with AR antagonists, androgen deprivation therapy (ADT) as well as for CRPC, and point towards novel therapeutic strategies. The understanding of individualized adaptation processes in PCa will lead to individualized treatment options in the future. 相似文献
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《Expert review of anticancer therapy》2013,13(9):1495-1508
Androgen receptor (AR) signaling is necessary for the development of prostate cancer. Androgen-deprivation therapy (ADT) for prostate cancer was described over 50 years ago and ADT remains the mainstay of systemic therapy. AR signaling remains intact as the disease evolves to castration-resistant prostate cancer (CRPC). Through cellular adaptations, CRPC continues to rely on androgens and AR growth signaling, and thus AR remains an important therapeutic target. CRPC cells upregulate enzymes used in androgen synthesis, thus providing an intracellular source of androgen despite systemic castration. Compounds in development, such as antiandrogens, lyase inhibitors, heat-shock protein-90 inhibitors, histone deacetylase inhibitors and others, will provide new tools to more effectively reduce ligand, inhibit AR and/or inhibit costimulatory pathways and result in improved clinical outcomes. 相似文献
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M Crespo G van Dalum R Ferraldeschi Z Zafeiriou S Sideris D Lorente D Bianchini D N Rodrigues R Riisnaes S Miranda I Figueiredo P Flohr K Nowakowska J S de Bono L W M M Terstappen G Attard 《British journal of cancer》2015,112(7):1166-1174
Background:
Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone.Methods:
CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide.Results:
AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra-patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis.Conclusions:
We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome. 相似文献15.
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Identification of the mechanisms that drive progression of metastatic castration-resistant prostate cancer (CRPC) has fostered interest since early androgen studies in the 1940s. Little knowledge has surfaced about the role mutations play in prostate cancer development. A group at the Michigan Center for Translation Pathology studied exomes of lethal, metastatic CRPC and documented the overall mutation rates. In classifying these mutations, the monoclonal cause of CRPC was recognized. Nine identified genes showed significant mutations. Six of these genes had previously been reported as mutated in prostate cancer. The analysis also found significantly mutated androgen receptor (AR) cofactors and linked proteins, including FOXA1 and MLL2. Another finding concerned an aberration in CHD1. Prostate cancers with deletions or mutations in CHD1 showed a strong correlation with ETS gene family fusion negative prostate cancers (96%). In profiling these exomes, this group provides an original method to identify deletions and mutations that drive CRPC progression. 相似文献
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我国前列腺癌发病率呈逐年上升趋势,且大多数前列腺癌患者就诊时已处于中晚期,虽然内分泌治疗可使多数患者的病情在一定程度上能得到控制和改善,但其中绝大多数患者发展为去势抵抗性前列腺癌(castration resistant prostate cancer ,CRPC)。 此类患者预后极差,治疗颇为棘手,因此迫切需要新的治疗策略。精准医学能够根据每位患者的基因特征指导临床个体化治疗。本文就CRPC发病机制和靶向治疗药物的研发、指导个体化治疗的临床试验进行综述,以总结和探讨CRPC精准医学研究的进展。 相似文献
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Tie Zhou Shengfei Qin Weidong Xu Shouyan Tang Guanghua Chen Song Li Jianguo Hou Xu Gao Guowei Shi Zhongquan Sun Jie Jin Lijun Chen Weibing Sun Ben Liu Jingen Wang Qinggui Meng Dongwen Wang Zhiquan Hu Dalin He Yong Yang Xishuang Song Cheng Fu Yinhuai Wang Dingwei Ye Wei Zhang 《International journal of cancer. Journal international du cancer》2023,153(4):792-802
We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177). 相似文献
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Anchit Khanna Jayant K. Rane Kati K. Kivinummi Alfonso Urbanucci Merja A. Helenius Teemu T. Tolonen Outi R. Saram?ki Leena Latonen Visa Manni John E. Pimanda Norman J. Maitland Jukka Westermarck Tapio Visakorpi 《Oncotarget》2015,6(23):19661-19670
Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients. CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer. 相似文献
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《Expert review of anticancer therapy》2013,13(9):1037-1048
Persistent androgen receptor (AR) axis is a functionally important pathway for prostate cancer cells and it is currently regarded as a critical therapeutic target. Although the impressive clinical activity of new hormonal agents, such as the second-generation AR antagonist enzalutamide (formerly MDV3100) and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone acetate (AA), in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises. To date, emerging hypotheses are different, but the mechanisms of resistance to these drugs have not yet been clarified. The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies. Understanding how the AR is activated may have clinical implications in defining which patients will respond to existing therapeutic agents and provide a proof for making novel strategies. 相似文献