去势抵抗性前列腺癌化疗耐药机制的研究进展

前列腺癌的发病率和死亡率逐年上升,去势治疗是中晚期前列腺癌的最主要治疗方法,但去势抵抗性前列腺癌为临床治疗难点,化疗虽为后续主要治疗手段,但易出现耐药。最新研究表明,去势抵抗性前列腺癌患者化疗后再使用抗雄激素药物能提高总生存率。本文就近年来去势抵抗性前列腺癌化疗耐药相关机制做一综述,探讨雄激素受体、自噬、JAK/STAT3信号通路在去势抵抗性前列腺癌发生化疗耐药过程中所发挥的调控作用。     

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。     

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。      

比卡鲁胺治疗雄激素非依赖性前列腺癌

雄激素非依赖性前列腺癌（androgen-independent prostate cancer，AIPCa）是前列腺癌治疗中的难点之一，在临床上AIPCa根据疾病发展的不同阶段可以再分为：雄激素非依赖性、激素敏感型前列腺癌，和雄激素非依赖性、激素不敏感型前列腺癌或称激素抵抗性前列腺癌。激素敏感型雄激素非依赖性前列腺癌对改变激素治疗方式仍敏感，因此，二线内分泌治疗是主要的治疗选择。比卡鲁胺（bicalutamide，康士德，casodex）是欧美常用的二线内分泌治疗药物之一，在临床上取得了一定的疗效。而国内报道极少。为观察比卡鲁胺的疗效，我们于2000年1月-2004年12月，用比卡鲁胺作为二线内分泌治疗药物，治疗AIPCa患者20例，对部分患者有效。     

雄激素阻断治疗后前列腺癌组织中肿瘤干细胞比例变化

目的 研究雄激素阻断治疗（androgen deprivation therapy ,ADT）对前列腺癌组织中肿瘤干细胞比例的影响,探讨激素非依赖性前列腺癌形成的机制。方法 实验分为ADT治疗组和无ADT治疗组,应用免疫荧光技术比较两组前列腺癌患者术前术后标本中肿瘤干细胞的比例变化。结果 无ADT组术前穿刺标本和前列腺根治切除术后标本肿瘤干细胞比例差异无统计学意义[（3.56±1.33）%vs. （3.78±1.39）%, n=9, t=-0.686, P=0.512] ,在ADT组,接受雄激素阻断治疗3月后,与穿刺标本比较,根治切除标本中前列腺癌肿瘤干细胞比例明显升高[（3.44±1.81）% vs. （9.22±1.71）% ,n=9,t=-6.353, P=0.000]。在癌旁组织,也可见ADT后干细胞标志的增加。结论 雄激素可能参与前列腺和前列腺癌组织中干细胞的分化;雄激素非依赖性前列腺癌的形成可能与前列腺癌肿瘤干细胞有关。     

雄激素剥夺疗法和免疫疗法在前列腺癌治疗中的研究进展

前列腺癌在美国成年男性中发病率位居第一，癌症相关致死率位居第二。雄激素剥夺治疗是最常用的前列腺癌治疗方法，而且通常伴随患者的终身治疗。雄激素和雄激素剥夺疗法对免疫系统有着重要的影响，在目前免疫治疗受到持续关注的情况下这一发现显得尤为重要。研究表明，雄激素剥夺治疗可能对免疫治疗起到促进或者抑制的作用。本文综述了不同类型雄激素剥夺治疗药物的作用机制，探讨了其对前列腺癌细胞及患者免疫系统的影响，以及联合使用雄激素剥夺药物和免疫治疗的前景，为前列腺癌的治疗提供了新的视野和思路。     

抗雄激素撤除综合征

目的 探讨抗雄激素撤除综合征的临床意义及特点，提高对抗雄激素撤除综合征的认识。方法 回顾性分析14例病人的资料，年龄70-79（平均74．9）岁。均经病理证实为前列腺癌，G23例，G39例。gleason评分7分1例，8分l例。初诊时C期10例，D期4例，D期均为骨转移。14例均用全雄激素阻断治疗，其中手术去势＋flutamide 12例，药物去势＋flutamide 2例。治疗5-84（平均37．7）个月后，因血PSA升高且血睾酮在去势水平而停用flutamide。停药前PSA3．2—40．8ng／mL，平均15．7ng／mL。停药后每月查血PSA1次。结果 停用flutamide后，6例病人血PSA较停药前下降，5例下降〉50％，如以血PSA下降〉50％为有效，则有效5例，有效率为36％。有效时间2．5撕（平均3．9）个月。结论 抗雄激素撤除综合征在用全雄激素阻断治疗的前列腺癌病人中有一定发生率，因此对用全雄激素阻断治疗有效的前列腺癌病人，当血PSA重新升高，并且血睾酮处于去势水平，应首先停用抗雄激素治疗。     

什么样的前列腺癌患者要进行化疗？

晚期前列腺癌经内分泌治疗后，多数在经历不同的缓解期（一般为2年左右）后将转为雄激素非依赖性前列腺癌，此时对各种内分泌治疗药物的治疗均无效。抗肿瘤化疗药物治疗前列腺癌，近几年发展迅速。全身化疗主要适用于晚期转移性前列腺癌，经内分泌治疗或放射治疗失败后，肿瘤进入了雄激素非依赖阶段的患者。     

PAK6对前列腺癌的双向调控作用

前列腺癌为一类男性患病率较高的癌症,对该癌症机制的认识以及治疗手段非常有限,在西欧和美洲男性中是一类致死率较高的癌症。随着科学研究的不断进展,p21活化激酶（PAK）蛋白家族在癌症中发挥的作用开始进入人们的视野。p21活化激酶6（PAK6）最初是以雄激素受体的配体结合域（LBD）上的氨基酸序列629～919,通过酵母双杂交识别出来的雄激素受体相关蛋白。而雄激素与雄激素受体在前列腺癌的发生与发展中发挥了十分重要的作用,因此 PAK6蛋白作为前列腺癌治疗的靶向蛋白被不断研究。本文主要介绍 PAK6在前列腺癌中的双向调节作用,包括通过磷酸化雄激素受体抑制雄激素受体向核内转移的抑癌作用,和通过抑制 BAD 凋亡通路、影响前列腺癌细胞生长周期以及促进前列腺癌细胞从细胞集落中脱离的促癌作用。同时 PAK6的表达水平和激酶活性的调节对 PAK6在前列腺癌中发挥作用具有十分重要的意义。激素与生长因素和内质网应激可能是提高 PAK6表达水平和激酶活性的两条途径。PAK6在前列腺癌中发挥的作用与其表达水平和激酶活性的调节机制对前列腺癌的治疗手段以及其治疗药物的靶向目标具有十分重要的意义。     

去势抵抗型前列腺癌的研究进展

前列腺癌（prostate cancer,PCa）的发病率在我国呈明显升高的趋势。前列腺癌发生、发展与糖皮质激素的水平有着显著的关系,其中内分泌及抗雄激素治疗是PCa治疗的重点,在治疗1～2年后导致的去势抵抗型前列腺癌（castrate resistant prostate cancer,CRPC）一直是临床研究的热点。本文总结了应用新一代的抗雄激素药物阿比特龙、恩杂鲁胺等,以为临床治疗选择提供依据。     

Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling

Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens in vitro using platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance.Abbreviations: ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; HR, high-risk disease; MS, mass spectrometry; T, testosterone     

Targeting persistent androgen receptor signaling in castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC), the invariably lethal phenotype of advanced prostate cancer, represents a clinical state defined by disease progression despite reduction of testosterone to castrate levels (i.e., ≤50 ng/dL). Although resistant to androgen-deprivation therapy (i.e., LHRH agonists/antagonists), CRPC continues to depend on the androgen receptor (AR)-signaling pathway. Supporting the importance of AR-signaling in a castration-resistant state, the next-generation AR-signaling inhibitors enzalutamide and abiraterone have been shown to afford a survival benefit in men with metastatic CRPC. However, primary and secondary resistance mechanisms to these agents inevitably drive continued disease progression—often as a result of re-activation of AR-signaling. With increased understanding of the mechanisms underlying how continued AR-signaling occurs in spite of drugs like abiraterone and enzalutamide, a new wave of therapies is emerging designed to more effectively target AR-signaling. This review will focus on the more clinically relevant mechanisms of CRPC drug resistance and our ongoing efforts to develop drugs to target these mechanisms.     

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.     

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。     

NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer

Castration resistance is a major issue during castration therapy for prostate cancer and thus more effective treatment are needed for castration-resistant prostate cancer (CRPC). NDRG2 (N-Myc downstream regulated gene 2), a recently identified tumor suppressor, was previously shown to inhibit the proliferation and invasion of prostate cancer, but whether NDRG2 is involved in CRPC remains to be known. Because androgen receptor (AR) axis plays an important role in castration resistance, we evaluate the role of NDRG2 in AR signaling and CRPC. Immunohistochemistry examination of prostate cancer tissues demonstrated that the expression of NDRG2 is negatively correlated with that of AR and c-Myc. Furthermore, AR negatively regulates NDRG2, as well as alters levels of c-Myc and prostate specific antigen (PSA). Forced expression of NDRG2 significantly inhibits the in vitro growth of androgen-dependent and castration-resistant prostate cancer cells; this was accompanied by alterations in PSA, but not by those of AR and c-Myc. Finally, by mimicking castration therapy in a xenograft mouse model, we showed that lentivirus-mediated NDRG2 overexpression efficiently overcomes castration resistance. Thus, by acting as a negative regulator downstream of AR, NDRG2 may emerge as a potential therapy molecule for CRPC.     

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.Subject terms: Prostate cancer, Chemotherapy     

Changing therapeutic paradigms in castrate-resistant prostate cancer

Prostate cancer is the most common cancer, and the second leading cause of death from cancer, in males in most Western countries. Advanced prostate cancer is initially sensitive to androgen deprivation therapy, but usually progresses to the castration-resistant state. There is now incontrovertible evidence that castration-resistant prostate cancer (CRPC) remains hormone driven, with intratumoral steroid synthesis fueling tumor growth. Several novel agents targeted androgen receptor signaling are currently being evaluated including abiraterone and MDV3100. Recent results of the phase III trial of abiraterone acetate in post-docetaxel patients has shown an overall survival benefit in advanced CRPC. This new treatment is likely to become a new standard of care for patients with metastatic CRPC.