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].     

多西紫杉醇治疗激素非依赖性前列腺癌临床研究新进展

预后较差的激素非依赖性的前列腺癌,目前的治疗方法主要是化疗.米托蒽醌和雌莫司汀都是已经FDA批准的可以用于治疗前列腺癌的化疗药物.两种药物与单用激素相比,未延长患者的生存时间.2004年全美临床肿瘤年会(ASCO)上,报告了两项多西紫杉醇联合化疗治疗激素难治性前列腺癌的临床研究,结果显示能明显改善生存.     

去势治疗诱导的神经内分泌前列腺癌的研究进展*

转移性前列腺癌行去势治疗（androgen-deprivation therapy ,ADT ）后将逐渐发展为去势抵抗性前列腺癌（castration-resistant prostate cancer ,CRPC）。 神经内分泌前列腺癌（neuroendocrine prostate cancer,NEPC）是CRPC的极差预后亚型,多由前列腺癌细胞发生神经内分泌分化（neuroendocrine differentiation ,NED ）引起,放化疗效果较差,平均生存期不到1 年,约占因CRPC患者死亡的25％,目前其分子机制研究较有限。进一步研究NEPC发生的分子机制将为NEPC治疗药物的开发与应用提供新的思路。      

去势难治性前列腺癌分子预后标志物研究进展

前列腺癌是老年男性常见的恶性肿瘤，内分泌治疗虽可使大多数患者的病情得到控制和改善，但在经过一段时间的缓解后，绝大多数患者会发展为预后极差的去势难治性前列腺癌（CRPC）。对CRPC患者如何实施个体化治疗，以最小的不良反应和最大的获益来延长生存已成为临床工作者亟待解决的难题。目前临床上采用的分级分期方法很难准确预测具有复杂生物学行为的CRPC患者的预后。近年许多肿瘤标志物相继被发现并用于CRPC患者的预后判断，本文对影响CRPC预后的分子标志物做一综述。      

去势抵抗性前列腺癌药物治疗现状与进展

前列腺癌发病率、死亡率逐年升高，是肿瘤防治最受关注的恶性肿瘤之一。去势抵抗性前列腺癌（castration-resistant prostate cancer，CRPC）患者的规范化药物治疗是提高患者生存时间、改善生存质量的关键方法。本文将就近年来有关CRPC药物治疗的现状及最新进展进行综述。      

转移性激素敏感性前列腺癌系统性全身治疗的研究进展

摘 要：初诊转移性前列腺癌的治疗以雄激素剥夺治疗(ADT)为主,但随着疾病进展都不可避免地发展为预后不良的转移性去势抵抗性前列腺癌。近年来,早期联合治疗在转移性激素敏感性前列腺癌的治疗方面取得了突破性进展,多项研究提示ADT联合多西他赛或醋酸阿比特龙加泼尼松龙能显著性改善患者的生存预后。同时,新药及新的治疗策略也在不断推陈出新,针对多种新型内分泌治疗及免疫治疗的探索性研究正在逐步开展。全文主要针对转移性激素敏感性前列腺癌系统性全身治疗的研究进展进行综述,探讨如何优化多种治疗选择达到患者的最大生存获益。     

外周血循环肿瘤细胞对前列腺癌预后判断价值的研究

前列腺癌是泌尿系统最常见的恶性肿瘤之一,居男性肿瘤特异性死亡率的第二位,且呈逐年上升趋势。相当一部分患者确诊时已失去手术治疗的最佳机会,这部分患者虽对内分泌治疗(去雄)有初效,但最终可发展为去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)。该类患者预后差,对治疗反应差异性大,中位生存时间数1~2年,且对治疗预后的评判也难以量化明确。近年来,循环肿瘤细胞(CTCs)检测计数,甲基化表型分析及标记物检测等研究对于肿瘤细胞迁移,预后评估,个体化治疗显现出重要意义。因此,作者就CTCs的总体概况及目前在前列腺癌中的临床应用进行总结,为CRPC的个体化治疗方向提供参考。     

雄激素受体在前列腺癌细胞中作用及其靶向治疗的研究进展

雄激素受体(androgen receptor, AR)在前列腺癌的发生发展中扮演重要角色。雄激素剥夺疗法(androgen deprivationtherapy, ADT)早期可成功抑制肿瘤的生长, 但最终导致肿瘤复发并进入激素抵抗阶段。AR对前列腺癌基质细胞起促进肿瘤增殖和转移作用, 是上皮腔样细胞的存活因子, 而对肿瘤干细胞样细胞及上皮基底细胞的增殖起抑制作用, AR在不同类型细胞中的不同作用向当前ADT传统的疗法提出挑战, 为发展新的治疗策略提供理论依据。目前以AR为靶点的靶向治疗药物研发也取得一些进展。本文就AR在前列腺癌不同类型细胞中的作用及靶向治疗方面的进展加以综述。      

晚期前列腺癌多发转移风险预测指标的探讨

目的:探讨年龄、Gleason评分、前列腺体积、治疗前血清PSA水平、雄激素阻断(ADT)后PSA水平、ECOG评分、是否有高血压、糖尿病和病理性骨折对晚期前列腺癌患者单发或多发转移的预测价值.方法:回顾性分析2005年1月至2011年8月收治的198例转移性前列腺癌患者的临床资料,应用χ2检验分析临床因素与转移部位数量的关系;多发转移的影响因素分析应用logistic回归分析;应用Kaplan-Meier 法和log-rank 检验进行生存分析.结果:晚期前列腺癌的Gleason评分8~10分(P<0.001)、ADT后PSA水平>0.2 ng/ml(P<0.001)、治疗前血清PSA水平>60 ng/ml(P=0.004)、ECOG评分≥ 2(P=0.002)和多发转移有显著的相关性;应用二维logistic回归分析研究这些变量对多发转移的影响,结果显示Gleason评分(P=0.022)、治疗前血清PSA水平(P=0.028)、ADT后PSA水平(P<0.001)和ECOG评分(P=0.001)对多发转移有显著影响;转移位置数量≥2个提示生化复发(多发:21个月 vs 单发:24个月)和生存时间(多发:36个月 vs 单发:45个月)均较短(P<0.001).结论:晚期前列腺癌的Gleason评分、治疗前血清PSA水平、ADT后PSA水平和ECOG评分与多发转移有显著正相关性;多发转移预示较短的生化复发和生存时间.     

内分泌治疗后进展为去势抵抗性前列腺癌的危险或保护因素分析CSCD

目的从前列腺癌的若干临床指标中,筛查早期(2年内)进展为去势抵抗性前列腺癌(CRPC)的可能危险及保护因素。方法确诊前列腺癌后的2年内发生去势抵抗的患者作为病例组(n=71),2年内未发生去势抵抗的患者作对照组(n=71),应用Logistic回归模型及生存分析筛选出可能的危险或保护因素。结果多因素Logistic分析:两组PSA最低值(PSA nadir)和到达最低值时间(TTN)差异具有统计学意义(均P<0.05)。TTN≤9月和>9月时,发生CRPC中位时间是8.29和16月;PSA nadir≤0.2 ng/ml和>0.2 ng/ml时,发生CRPC中位时间是12和9月。结论TTN可能是早期进展为CRPC的保护因素,PSA nadir可能是早期进展为CRPC的独立危险因素,其中TTN≤9月和PSA nadir>0.2 ng/ml是CRPC的危险因素。     

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.     

Broadening horizons in medical management of prostate cancer

HORMONAL THERAPY: Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 1-2 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration-resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response. CHEMOTHERAPY: Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA). CONCLUSION: Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care.     

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.     

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。     

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     

Current,new and novel therapy for castration-resistant prostate cancer

Androgen deprivation therapy is the standard of care for the initial treatment of metastatic prostate cancer. However, the majority of these patients live long enough to experience disease progression despite castration. This scenario is defined as castration-resistant prostate cancer (CRPC) and has a poor outcome and limited options for treatment. First-line treatment after hormonal therapy failure include secondary hormonal manipulation and docetaxel. Advances in the understanding of the molecular mechanisms underlying CRPC have translated into a recent increase in the number of effective systemic agents, and some of them have been already approved as first and second-line treatment. Despite these advances, the median survival in the first-line setting of metastatic CRPC is approximately 20 months and in the postdocetaxel setting is approximately 15 months. Promising and necessary new therapies in Phase III trials include hormonal agents, new cytotoxics agents, as well as other immunotherapeutics and antiprostate-specific membrane antigen therapies.     

Androgen receptor: role and novel therapeutic prospects in prostate cancer

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.     

前列腺癌雄激素剥夺治疗的新思路——睾酮最大控制临床研究新进展

前列腺癌是常见的男性恶性肿瘤之一,其发病率位居男性恶性肿瘤第二位。前列腺癌的发病率居于所有男性恶性肿瘤首位。中国男性的前列腺癌发病率低于欧美国家,但随着生活方式、饮食习惯的西化以及人均寿命延长,前列腺癌的发病率也呈现逐年升高的趋势。雄激素受体（androgen receptor,AR）在前列腺癌的发生、发展过程中扮演着重要角色,抑制AR信号转导通路是前列腺癌治疗的基础,比如在去势抵抗性前列腺癌（castration-resistant prostate cancer,CRPC）治疗中,使用AR拮抗剂能够竞争性结合AR并阻断内源性雄激素的结合,从而干扰雄激素依赖的细胞下游反应,阻止前列腺癌的进展。雄激素剥夺治疗（androgen deprivation therapy,ADT）是前列腺癌治疗的基石,国内专家共识中前列腺癌去势治疗有效定义的睾酮（testosterone,T）水平为低于50 ng/dL。随着研究的深入,越来越多的研究表明T低于20 ng/dL的患者临床预后更佳：T ＜ 20 ng/dL时可以诱导包括雄激素敏感和部分雄激素不敏感亚群细胞的死亡,在治疗间隙细胞增殖时可以获得雄激素高度敏感的细胞群,从而延长了去势抵抗的时间。如果不能达到T ＜ 20 ng/dL,可能会导致部分雄激素不敏感的亚群持续存在,这些亚群在再次治疗后会快速增殖,加速肿瘤向去势抵抗发展。目前控制T水平的促性腺激素释放激素激动剂（gonadotropin-releasing hormone agonist,GnRHa）的有效性和安全性在研究中和临床上均得到了明确的验证,在药物层面上提供了控制T ＜ 20 ng/dL的临床可行性。通过总结T水平与ADT新进展,探讨最大限度控制T水平与前列腺癌治疗中患者受益、药物疗效及安全性的关系。     

Metastatic castration-resistant prostate cancer (CRPC): preclinical and clinical evidence for the sequential use of novel therapeutics

With five novel therapies shown to improve survival in metastatic castration-resistant prostate cancer (CRPC) in the last 3 years, patients are now living longer and experiencing better quality of life. Since docetaxel became standard of care for men with symptomatic metastatic CRPC, three artificial treatment “spaces” have emerged for prostate cancer drug development: pre-docetaxel, docetaxel combinations, and following docetaxel. Multiple therapies are currently under development in both early and late stage CRPC. Additionally, the novel agents abiraterone, radium-223, cabazitaxel, and enzalutamide have all been approved in the post-docetaxel setting. Strategies for patient selection and treatment sequencing are therefore urgently required. In this comprehensive review, we will summarize the preclinical and clinical data available with regards to sequencing of the novel treatments for CRPC.