去势抵抗性前列腺癌新型内分泌治疗耐药机制研究进展

前列腺癌是男性泌尿生殖系统最常见的恶性肿瘤之一,雄激素在其发生发展中都扮演着重要角色。经去势治疗(ADT)后绝大多数前列腺癌都会进展成为去势抵抗性前列腺癌(CRPC)。肾上腺来源的雄激素和(或)雄激素受体(AR)的改变(包括AR基因扩增)驱动了瘤内雄激素的合成,进而重新雄激素轴信号通路。目前,阿比特龙、恩扎鲁胺等抗雄激素治疗药物都是CRPC患者的一线治疗用药。但是,治疗一段时间后患者仍然会出现耐药和疾病进展。因此,明确CRPC患者抗雄激素治疗耐药机制可以为克服CRPC治疗耐药和改善CRPC患者的预后提供契机。     

一种新型的治疗去势抵抗性前列腺癌的方法——双极雄激素治疗

双极雄激素治疗(BAT)是去势抵抗性前列腺癌(CRPC)的新型治疗方法,可显著降低患者血清前列腺特异性抗原(PSA)水平,且具有良好的安全性。笔者结合近期国内外临床试验,对BAT提出的背景、机制、发展进程及前景作一综述。     

抗雄激素撤退治疗去势抵抗性前列腺癌的疗效分析

目的 观察抗雄激素撤退治疗去势抵抗性前列腺癌(CRPC)的疗效,并分析影响疗效的预测因素.方法 对经持续性最大限度雄激素阻断疗法治疗后前列腺特异抗原(PSA)进行性升高的前列腺癌患者48例采用抗雄激素撤退治疗,氟他胺停用4周,比卡鲁胺停用8周.以血清PSA的变化作为主要观察指标,观察治疗前后患者血清PSA的变化情况.结果 抗雄激素撤退治疗后,共12例(25％)患者出现PSA下降≥50％,疾病缓解的中位有效时间为(4.0±2.0)个月.抗雄激素撤退治疗是否有效与治疗前患者一般特征无关.结论 抗雄激素撤退治疗对部分CRPC患者有效.     

转移性去势抵抗性前列腺癌临床治疗标志物——雄激素受体剪接变异体7

随着越来越多的转移性前列腺癌患者对去势治疗抵抗,进入去势抵抗性前列腺癌(CRPC)阶段,治疗方案的合理选择及对治疗效果的预测变得越来越重要。大量研究发现雄激素受体变异体7(ARV7)参与CRPC发生与进展的过程。研究发现ARV7在CRPC中表达水平明显高于激素敏感性前列腺癌,在对阿比特龙、恩扎鲁胺治疗抵抗以及紫杉烷类药物化疗逃逸的机制中发挥了重要作用。此外,部分临床研究发现,ARV7的水平可提示不同治疗方案的预后:循环肿瘤细胞(CTC)ARV7阴性预示新型内分泌治疗与紫杉烷类化疗效果有效,而CTC ARV7阳性则预示新型内分泌治疗效果不佳。这些发现预示ARV7可成为临床医生对于CRPC治疗方案的选择以及判断预后等方面的生物标志物。     

去势抵抗性前列腺癌的治疗进展

前列腺癌为常见男性实体器官恶性肿瘤,具有较高发病率和死亡率。转移性去势抵抗性前列腺癌(CRPC)是多数前列腺癌患者病情发展的转归,其临床治疗效果及预后较差,中位总生存期不足2年。部分CRPC患者因前期雄激素剥夺治疗或化学治疗发生耐药抵抗,因此制定有效的治疗方案尤为重要。近年临床用于治疗CRPC的新型内分泌药物主要有醋酸阿比特龙、恩扎卢胺及阿帕他胺等,而靶向治疗和免疫治疗等新疗法也在研发中。本文对CRPC治疗现状及进展进行了总结。     

前列腺癌双极雄激素治疗的研究进展

双极雄激素治疗(bipolar androgen therapy,BAT)是去势抵抗性前列腺癌(castration resistant pros-tate cancer,CRPC)的新疗法,可显著降低部分患者血清前列腺癌特异性抗原(prostate specific antigen,PSA)水平、提高患者生活质量和恢...     

恩扎卢胺一线治疗去势抵抗性前列腺癌

本文报道1例75岁合并多种心血管疾病的前列腺癌患者,临床分期为T 3bN 1M 0期。采用雄激素剥夺治疗(ADT)(戈舍瑞林+比卡鲁胺)并规律随访,第13个月开始PSA缓慢升高,至第17个月时考虑进展至去势抵抗性前列腺癌(CRPC)。结合患者合并多种心血管疾病,选择一线应用恩扎卢胺治疗,病...     

雄激素受体信号通路与去势抵抗性前列腺癌

前列腺癌在美国男性中发病率居首位,致死率居第二位。随着人口老龄化进程加剧及饮食结构改变,我国前列腺癌的发病率也逐渐增加。局限性前列腺癌常规行根治性前列腺切除术或放射治疗,而对于进展期患者则需要接受雄激素阻断治疗（androgen deprivation therapy,ADT）。     

去势抵抗性前列腺癌的治疗新进展

随着人们生活方式的改变以及前列腺特异性抗原筛查的普及,前列腺癌的诊断和治疗更为重要。尽管内分泌治疗对于进展性前列腺癌有治疗效果,但最终会进展为去势抵抗性前列腺癌,从而严重影响患者的生存期。近年来,研究者对于去势抵抗性前列腺癌的治疗做出了巨大努力,包括新的内分泌治疗、细胞毒性的化学治疗、免疫治疗以及以骨转移为靶点的治疗方式逐步问世,本文就这些新的治疗进展进行综述,以期为临床医生及进展性前列腺癌患者提供更多的治疗选择,延长总体生存期,提高生活质量。     

去势抵抗前列腺癌治疗现状及研究进展

前列腺癌经传统的雄激素剥夺治疗后,常转归为去势抵抗性前列腺癌从而影响患者的生活质量。目前,关于CRPC的治疗是研究热点之一,虽然近年来去势抵抗前列腺癌的治疗取得了很大的进展,但是针对去势抵抗前列腺癌治疗目前缺乏行之有效的方法使患者获得满意的生存时间。本文就CRPC的治疗进行综述,为临床对患者行治疗提供参考。     

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（~-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （OS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.     

Practical aspects of metastatic castration-resistant prostate cancer management: patient case studies

Interactive case studies formed a key feature of the third annual Interactive Genitourinary Cancer Conference held in April/May 2011 in Budapest, Hungary. These cases were used to discuss the practical aspects of the management of metastatic castration-resistant prostate cancer (mCRPC). Particular emphasis was placed on audience participation with potential management options posed as interactive questions to the delegates. This paper summarises these case studies and the related discussion. Docetaxel is the standard first-line chemotherapeutic agent for patients with mCRPC and, until recently, second-line therapeutic options were limited. Results from the recently completed TROPIC trial showed a statistically and clinically significant improvement in overall survival with the microtubule inhibitor cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to be well tolerated and has been approved in Europe and the USA as second-line chemotherapy for mCRPC. Prognostic factors have a potential benefit in individualised patient management in mCRPC. Pretreatment prognostic factors, including PSA doubling time, pain, visceral metastases, anaemia and progression of osseous metastases, have been shown to predict survival outcomes and can be used to guide treatment strategies, including appropriate timing of chemotherapy. Multiple treatment options and significant heterogeneity among patients with advanced prostate cancer necessitate multidisciplinary team management in addition to patient education, as part of a patient-centred approach. The development of second-line chemotherapeutic agents together with the use of prognostic factors and a patient-centred multidisciplinary team approach provide encouraging new management prospects for patients with mCRPC.     

非编码RNAs在去势抵抗性前列腺癌中的研究进展

非编码RNAs(ncRNAs)是一大类不编码蛋白的RNA分子,它们从多层面调控基因的表达,影响机体细胞的代谢、增殖、分化、凋亡和肿瘤的发生、发展。部分发挥癌基因作用的ncRNAs如miR-19a、miR-125b、miR-616、miR-7、miR-221、MALAT-1、PRNCR1等在去势抵抗性前列腺癌(CRPC)组织或细胞系中表达上调,促进CRPC的发生、发展;而另一部分发挥抑癌基因作用可抑制或延缓CRPC发生、发展的ncRNAs如miR-185、miR-342、miR-15、miR-16、miR-146等却表达下调;此外,部分ncRNAs如miR-7、miR-19a、miR-125b、miR-221、MALAT-1等在血清或组织中差异表达可作为CRPC早期诊断及预后判断的生物学标志物。本文就这些ncRNAs在CRPC发生、发展、诊断及预后中的作用及研究进展进行了综述。     

Optimal treatment for castration-resistant prostate cancer

The review article of treatments for castration-resistant prostate cancer （CRPC） by Sartor and Gillessen describes available sequencing data in detail with outlines of each agent.~ Currently, the efficacy of docetaxel, radium-223, sipuleucel-T, abiraterone and enzalutamide （this is upcoming） as front-line agents and cabazitaxel, radium-223, abiraterone and enzalutamide as post-docetaxel agents have been confirmed by phase III randomized controlled trials （RCTs）. While the development of treatment options should be of great benefit to CRPC patients, physicians may need to pay attention to patient selection for each treatment as these agents have not been compared with one another by head-to-head RCT.     

去势抵抗性前列腺癌治疗的循证实践

目的:以1例去势抵抗性前列腺癌(CRPC)患者的治疗为例,阐述循证实践的具体步骤和内容。方法:针对患者病情提出临床问题,系统检索Pub Med、EMBASE、Cochrane Library、Clinical Trial Registries等数据库,检索时限截至2014年12月,查找相关的研究证据,并对证据进行质量评价及应用。结果:患者病情得到缓解,治疗有效。结论:开展循证实践需要结合患者病情、研究证据和患者意愿,并遵循一定的步骤。     

Androgen receptor and prostate cancer

Since the original observations of Huggins and Hodges that prostate cancers are androgen dependent, androgen ablation therapy has been the gold standard for the treatment of advanced prostate cancer (CaP). Androgen receptor (AR) is believed to play critical roles in the development and progression of CaP. Treatment for neoadjuvant, adjuvant and recurrent disease all center on the regulation and manipulation of the androgen pathway, in which AR plays an integral role. Recent discoveries that frequent overexpression of ETS-related proto-oncogenes may be driven by AR as a consequence of common genomic rearrangements can hold the key towards the understanding of early phases of prostate cancer. Furthermore, AR function evolves as the cell changes towards a clinically androgen depletion independent state. Comprehension of AR function, regulation and abnormalities are increasingly refined towards the understanding of the role of AR in CaP, and in therapeutic applications. Development of future therapy for CaP will be aided by improving the knowledge of dysfunctions of AR and its network in prostate cancer. This review focuses salient features of AR and on the recent advances addressing AR dysfunctions in prostate cancer.     

The role of microRNA in castration-resistant prostate cancer

IntroductionCastration-resistant prostate cancer (CRPC) has a historically low median survival rate, but recent advances and discoveries in microRNAs (miRNAs) have opened the potential for new prognostication modalities to enhance therapeutic success. As new chemotherapies and immunotherapies are developed, there is an increasing need for precision and stratification of CRPC to allow for optimization and personalization of therapy.MethodsA systematic literature review was conducted via electronic database resulting in the selection of 42 articles based on title, abstract, study format, and content by a consensus of all participating authors. Most selected articles were published between 2002 and 2013. In this review, we discuss the robustness of miRNAs as a biomarker platform, miRNAs associated with prostate cancer, and recent discoveries of miRNA associations with CRPC.ResultsThe associations discovered have been of interest owing to the ability to differentiate between CRPC and localized prostate cancer. With the evaluation of multiple miRNAs, it is possible to provide a profile regarding tumor characteristics. Furthermore, actions of miRNAs on CRPC tumor cells have the ability to suppress metastatic phenotypes.ConclusionmiRNAs may have a growing role in CRPC prognostication and may potentially transform into a therapeutic potential.