雄激素受体在去势抵抗性前列腺癌进展中的作用及研究进展

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。     

去势抵抗性前列腺癌的治疗进展*

去势抵抗性前列腺癌是一种致死性疾病,进展快,常伴随着转移,预后极差,死亡率接近100% ,患者中位生存时间少于20个月,是前列腺癌治疗的热点和难题,其发生发展机制尚不明确。近些年来涌现出许多治疗去势抵抗性前列腺癌的新方法,包括新型雄激素受体拮抗剂、免疫治疗、紫杉烷类化疗药物、抗血管生成药物、放射性核素、骨靶向药物以及各疗法联合应用等,改善了患者的生存期。本文就去势抵抗性前列腺癌的治疗进展进行综述。      

前列腺癌中雄激素受体的表观遗传学研究进展*

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。      

前列腺癌干细胞与去势抵抗性前列腺癌放射性耐受的研究进展

前列腺癌经过去势治疗后有进展为去势抵抗性前列腺癌的可能。去势抵抗性前列腺癌对临床医生最大的挑战为其治疗抵抗特性。针对放疗耐受,相关研究认为与前列腺癌干细胞及前列腺癌干细胞相关miRNA相关。下文从去势抵抗性前列腺癌进展机制、前列腺癌干细胞及前列腺癌干细胞相关miRNA等方面介绍去势抵抗性前列腺癌放射性耐受的研究进展。     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标北大核心CSCD

0引言雄激素和雄激素受体（androgen receptor,AR）通路激活在前列腺癌的发生、发展中具有重要作用。因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法（androgen deprivation therapy,ADT）一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80%的患者不可避免的发展为去势抵抗性前列腺癌.     

转移性前列腺癌的内分泌治疗

雄激素与正常前列腺细胞与前列腺癌细胞的生长存在密切关系。目前，内分泌治疗目前仍是转移性前列腺的最有效治疗手段，其目的在于减少或消除雄激素对前列腺生长的促进作用，从而缓解转移性前列腺癌的症状。转移性前列腺癌的内分泌治疗通常包括手术去势与药物去势。药物去势通过使用雌激素类药物、抗雄激素类药物或黄体素释放激素类似物等药物以阻断雄激素与雄激素受体的结合或减少体内雄激素的产生。以非甾体类抗雄激素药物联合手术去势或LHRH类似物为方案的雄激素完全阻断治疗可阻断睾丸和肾上腺分泌的所有睾酮对前列腺的作用，但其效果是否优于单一药物去势治疗尚无定论。二线内分泌治疗，包括抗雄激素药物撤停、抗雄激素药物治疗、雌激素药物治疗、P450酶抑制剂治疗及皮质类固醇类药物治疗对初始内分泌治疗失效后的“激素非依赖性”前列腺癌仍具一定疗效，且因其毒副作用较少，应于全身化疗前优先采用。     

前列腺特异性启动子在慢病毒介导基因治疗中的研究进展

前列腺癌多发生于老年男性,其发病率和死亡率正在逐年上升。对于早期前列腺癌,采用阻断雄激素的去势治疗可以有效抑制肿瘤生长,但在治疗2～3年后大部分进展为去势抵抗性前列腺癌,这是导致患者死亡的主要原因。目前,对晚期尤其是去势抵抗性前列腺癌尚缺乏有效的治疗策略,随着生物技术的兴起与发展,针对恶性肿瘤的生物靶向治疗研究日趋深入和成熟,其中慢病毒介导的基因治疗成为研究的热点。运用特异性启动子调控相关基因的表达,可以进一步提高抗肿瘤的靶向性和安全性。本文就目前在基础研究中,前列腺特异性启动子在慢病毒介导下基因靶向治疗前列腺癌的研究现状进行综述。     

抗雄激素药物治疗去势抵抗型前列腺癌的机制研究进展

去势抵抗型前列腺癌（castration-resistant prostate cancer ,CRPC）是指经内分泌治疗产生耐药并继续发展的致命性前列腺癌,雄激素受体（androgen receptor,AR）激活途径仍是这一阶段前列腺癌发展的驱动机制,因此抗雄激素治疗仍然是重要的治疗手段之一。虽然许多新型抗雄激素治疗药物在临床治疗中显示了显著的疗效,但同时耐药也频繁出现。本文就近年来几种主要抗雄激素治疗药物的作用及相应的耐药机制进行综述。      

比卡鲁胺联合化疗治疗去势抵抗性前列腺癌的疗效分析

目的探讨比卡鲁胺联合化疗治疗去势抵抗性前列腺癌(CRPC)的疗效。方法选择2007年3月至2008年12月间收治的30例CRPC患者,采用比卡鲁胺作为二线抗雄激素药物,与多西紫杉醇、泼尼松化疗联合治疗,观察30例患者临床治疗效果及不良反应的发生情况。结果 30例CRPC患者经过比卡鲁胺联合化疗治疗方案治疗后,28例患者前列腺特异性抗原(PSA)反应,软组织及骨转移病灶缩小,临床症状改善,临床治疗有效率为93.3%,生存时间为(32.5±3.5)个月。2例治疗无效,8个月后死亡。另外,27例(90.0%)出现一定程度的骨髓抑制,白细胞及血小板水平降低,但经过升血象治疗后正常。无心脏毒性或肾功能损伤病例。结论比卡鲁胺联合多西紫杉醇、泼尼松化疗对去势抵抗性前列腺癌患者治疗有效,且不良反应少,值得推广应用。     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标

0 引言 雄激素和雄激素受体(androgen receptor,AR)通路激活在前列腺癌的发生、发展中具有重要作用.因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法(androgen deprivation therapy,ADT)一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80％的患者不可避免的发展为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC),生存期不超过2年[1-2].最近研究表明,前列腺癌细胞自身获得经由胆固醇从头合成雄激素的能力以及肿瘤利用肾上腺来源的激素前体转化为雄激素是前列腺癌进展为CRPC的关键因素[3-6].     

Cabazitaxel in metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Prior to 2010, docetaxel chemotherapy was the only treatment shown to improve overall survival, symptom control and quality of life in patients with CRPC. Research efforts focused on overcoming chemoresistance to taxanes eventually led to the development of multiple novel anti-tumor agents, including cabazitaxel. Cabazitaxel has recently been shown to significantly improve overall survival compared with mitoxantrone in a large multicenter Phase III study. This article details the preclinical and clinical development of cabazitaxel and discusses the importance of this novel chemotherapy in CRPC. The authors also discuss the challenges now facing the future use of cabazitaxel in CRPC, including the determination of the optimal dose of cabazitaxel in patients with advanced CRPC, the ideal sequencing of cabazitaxel relative to other anti-tumor treatments, appropriate patient selection and novel strategies for the assessment of treatment response.     

New strategies for medical management of castration-resistant prostate cancer

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.     

去势抵抗性前列腺癌的药物治疗现状

雄激素剥夺疗法(ADT)一直是晚期前列腺癌的代表性疗法。当前列腺癌进展为去势抵抗性前列腺癌(CRPC)时,ADT的抗性也随之出现。目前,多西他赛是首个被美国食品药品监督管理局(FDA)批准用于CRPC的细胞毒性化疗药物。另外,还有阿比特龙、恩杂鲁胺等药物也获得FDA批准,且这些药物都显示出良好的生存获益。本文对这些疗法的临床试验和生存获益进行了回顾,并对这一领域的新兴药物进行了讨论。本综述将对CRPC的药物治疗现状进行陈述,并为临床用药提供参考。     

Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies

Prostate cancer is androgen-dependent in its early stages and androgen deprivation therapy represents the most effective first-line therapeutic approach. However, after an initial remission, prostate cancer progresses towards the castration resistant prostate cancer (CRPC) stage, with increased malignancy and resistance to conventional chemotherapy.     

Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen‐deprivation therapy, but invariably progresses to the castration‐resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen‐deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first‐line treatment in patients with castration‐resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)–prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone–prednisone. Several other novel agents are currently being evaluated, including sipuleucel‐T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell‐based immunotherapy sipuleucel‐T produces longer OS times in chemotherapy‐naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.     

Tasquinimod: A Novel Angiogenesis Inhibitor–Development in Prostate Cancer

Castration resistant prostate cancer (CRPC) treatment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel, sipuleucel-T, abiraterone and enzalutamide. Though androgen deprivation and chemotherapy remain the main therapeutic approaches for this disease, a series of targeted agents is also in development for the treatment of CRPC. Tasquinimod is a quinolone-3-carboxamide with antiangiogenic and antitumor activity in preclinical models of prostate cancer. A recent Phase II trial with this agent has demonstrated a significant clinical activity in asymptomatic or minimally symptomatic, chemotherapy-naïve, CRPC patients. A confirmatory Phase III trial of tasquinimod in prostate cancer is underway. Because of its antiangiogenic and immunomodulatory properties tasquinimod represents a novel targeted therapy with a unique mechanism of action.     

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

Prostate cancer is the most common cancer in men in Europe and the United States, and the third leading cause of death from cancer in Europe. Survival of prostate cancer cells is dependent on the activation of androgen receptors (AR), that are overexpressed in this tumor. Furthermore, ~90% of prostate cancer patients that respond to first-line androgen deprivation therapy (ADT) undergo rapid progression. This condition is defined as castration-resistant prostate cancer (CRPC). Docetaxel-based regimens significantly improve overall survival (OS) in patients with CRPC and represent the only treatment strategy approved by the Food and Drug Administration (FDA). Recently, abiraterone (second hormonal therapy) and cabazitaxel (new taxane) have been shown to improve survival in patients with CRPC who progressed following docetaxel-based chemotherapy. Vaccine therapy has also been demonstrated to improve OS in patients with asymptomatic or minimally symptomatic metastatic CRPC. Additional therapeutic targets have been analyzed in prostate cancer, including apoptosis, angiogenic receptors, vitamin D and Src pathways. Several phase II studies are ongoing. The high frequency of prostate cancer-related metastatic bone disease has led to consider this pathway as a therapeutic target. To this end, several bone-targeted agents have been investigated, most notably zoledronic acid, which is highly effective at stabilizing the bone and preventing skeletal complications. More recently, a nuclear factor-β ligand (RANKL) inhibitor, denosumab, has been developed for the treatment of bone metastases.     

多学科综合治疗——改善高危前列腺癌患者的预后

手术和放疗是局限性前列腺癌主要的治疗方法,但对于高危前列腺癌单用局部治疗预后不佳,超过50％的患者会复发。手术、放疗、内分泌治疗和化疗的联合应用目前被认为是提高高危前列腺癌疗效的重要途径。本文总结了目前高危前列腺癌综合治疗的相关文献,期望能为我国高危前列腺癌综合治疗方案的选择提供借鉴和参考。     

Class III beta-tubulin expression predicts prostate tumor aggressiveness and patient response to docetaxel-based chemotherapy

Expression of class III β-tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies, but its use as a biomarker of tumor behavior in prostate cancer (PCa) remains largely unexplored. Here, we describe βIII-tubulin immunohistochemical staining patterns of prostate tumors obtained from a broad spectrum of PCa patients, some of whom subsequently received docetaxel therapy for castration-resistant PCa (CRPC). Elevated βIII-tubulin expression was significantly associated with tumor aggressiveness in PCa patients with presumed localized disease, as it was found to be an independent marker of biochemical recurrence after treatment. Additionally, βIII-tubulin expression in tumor cells was an independent predictor of lower overall survival for patients receiving docetaxel-based chemotherapy for CRPC. Manipulation of βIII-tubulin expression in human PCa cell lines using a human βIII-tubulin expression vector or βIII-tubulin small interfering RNA altered cell survival in response to docetaxel treatment in a manner that supports a role for βIII-tubulin expression as a mediator of PCa cell resistance to docetaxel therapy. Our findings suggest a role for βIII-tubulin as candidate theranostic biomarker to predict the response to docetaxel-based chemotherapy as well as to target for treatment of docetaxel-resistant CRPC.