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。     

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。      

多西他赛治疗前列腺癌的研究进展

多西他赛是一种细胞毒性抗肿瘤药物,在前列腺癌中的疗效确切。对于激素敏感性前列腺癌,能明显提高高负荷转移性前列腺癌患者的总体生存期。对于去势抵抗性前列腺癌,可延缓癌症相关症状的进展。但多西他赛的严重不良反应常导致其使用受限制,适时联合用药可使患者获得较高的生存效益。本文对多西他赛治疗各类前列腺癌及其不良反应、应用时机的研究进行综述,以期为临床前列腺癌化疗提供参考。     

沙利度胺联合化疗治疗骨转移去势抵抗性前列腺癌的疗效观察

背景与目的:多西他赛联合泼尼松治疗可延长转移性去势抵抗性前列腺癌患者的生存期,血管生成抑制剂也可抑制肿瘤生长,联合治疗的疗效目前仍不明确.该研究旨在观察沙利度胺联合多西他赛和泼尼松治疗骨转移的去势抵抗性前列腺癌的近期临床疗效.方法:收集2008年12月—2015年6月南京军区福州总医院收治的骨转移去势抵抗性前列腺癌患者78例,其中40例作为对照组给予多西他赛和泼尼松方案化疗,38例作为观察组在对照组的基础上给予沙利度胺联合化疗,观察两组有效率、骨痛缓解率、前列腺特异性抗原(prostate specific antigen,PSA)无进展时间、无疾病进展时间及总生存时间,并评价不良反应.结果:观察组有效率为65.79%,PSA无进展时间为4.13个月,无疾病进展时间为4.25个月,骨痛缓解率为86.84%;对照组有效率为40.00%,PSA无进展时间为3.54个月,无疾病进展时间为3.75个月,骨痛缓解率为60.00%,观察组均高于对照组,差异有统计学意义(P<0.05).治疗后两组总生存时间、患者恶心呕吐及白细胞下降等不良反应发生率比较,差异无统计学意义(P>0.05).结论:沙利度胺联合化疗治疗骨转移的去势抵抗性前列腺癌近期临床效果满意,安全,不增加不良反应,具有较高的临床应用价值.     

去势抵抗性前列腺癌差异表达基因的生物信息学分析

目的:基于大数据从分子水平筛选原发性前列腺癌与去势抵抗性前列腺癌的差异表达基因,探寻前列腺癌细胞从雄激素依赖到抵抗状态发展过程中的可能机制,为去势抵抗性前列腺癌的诊疗提供靶点。方法:在NCBI的公共基因芯片数据库（GEO）中下载原发性及去势抵抗性前列腺癌相关芯片数据（GSE74367、GSE66187和GSE126881）,利用limma包进行标准化和基因差异分析,接着采用clusterProfiler包分别进行GO功能和KEGG通路分析。将P＜0.05和|logFC|>2作为筛选标准,使用vennDiagram包合并基因集,找到3个芯片的共同差异基因,并利用clusterProfiler包对共同上调或下调基因进行基因集富集分析。结果:GSE74367和GSE66187中的差异基因主要与RNA分解代谢与剪接功能相关,主要富集于核糖体生物发生通路。GSE126881的差异基因主要与干扰素γ反应功能有关,主要富集表达于化学抗癌、类固醇激素生物合成以及视黄醇、细胞色素P450、抗坏血酸和醛酸的代谢过程。3个芯片的共同上调基因为SLC16A3,共同下调基因为DDX53。GSEA分析发现,SLC16A3上调时,果糖、甘露糖和磷酸戊糖代谢与细胞周期相关基因集显著上调;DDX53下调时,原发性免疫缺陷通路、趋化因子与细胞黏附分子等相关基因集下调,而磷酸戊糖途径、细胞周期和蛋白质外排等过程的相关基因集上调。结论:通过对3个去势抵抗性前列腺癌相关GEO芯片数据的生物信息学分析,我们发现SLC16A3的上调和DDX53的下调可能在原发性前列腺癌发展为去势抵抗性前列腺癌的过程中发挥重要作用。     

达罗他胺治疗前列腺癌真实世界临床观察

目的 评价真实世界中达罗他胺治疗前列腺癌患者的早期疗效和安全性。方法 回顾性分析2022年1月至10月在郑州大学第一附属医院接受达罗他胺治疗的23例前列腺癌患者的临床资料,治疗方案为手术去势或药物去势联合达罗他胺治疗,主要观察指标为用药后患者的前列腺特异性抗原(PSA)、影像学反应以及药物相关不良反应。结果 局限前列腺癌、转移性激素敏感性前列腺癌(mHSPC)患者应用达罗他胺治疗PSA缓解率达100.0%,非转移去势抵抗性前列腺癌(nmCRPC)患者应用达罗他胺治疗PSA缓解率为50.0%,转移去势抵抗性前列腺癌(mCRPC)患者应用达罗他胺治疗PSA缓解率为66.7%。共随访到12例患者的影像学资料,其中4例局限前列腺癌患者、7例mHSPC患者的肿瘤病灶显著缩小,1例nmCRPC患者出现多处新发骨转移病灶,进展为mCRPC。不良反应主要有疲乏4例、潮热2例、盗汗2例、血脂升高2例、血糖升高1例、四肢疼痛1例、食欲欠佳1例,均为Ⅰ、Ⅱ级,无Ⅲ级以上不良反应发生。结论 达罗他胺治疗前列腺癌具有较好的早期疗效,且安全性良好。     

溶瘤腺病毒治疗前列腺癌研究进展

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。     

转移性去势抵抗性前列腺癌化疗后预后的影响因素

目的探讨采用多西紫杉醇化疗的转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer,MCRPC)患者预后影响因素。方法以转移性去势抵抗性前列腺癌患者46例作为观察对象,记录患者化疗前年龄、Gleason评分、前列腺特异抗原(prostate-specific antigen,PSA)值、血常规等基线情况及激素敏感时间。结果患者总生存时间为3~45个月,平均生存期为(21.34±2.13)个月,中位生存时间为19.36个月;Cox回归结果提示,Gleason评分、血红蛋白水平、激素敏感时间与患者生存时间相关,RR值分别为1.782、2.363和2.012,且P<0.05。结论多西他赛化疗前Gleason评分、血红蛋白浓度及激素敏感时间,是转移性去势抵抗性前列腺癌患者的预后因素。     

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。      

Immune-checkpoint inhibitors and metastatic prostate cancer therapy: Learning by making mistakes

Despite advances in metastatic prostate cancer therapy, expected survival for patients in the castration-resistant phase of disease is poor. Immune-checkpoints inhibitors significantly prolonged life expectancy in some solid tumors and have been evaluated also in advanced stage prostate cancer. The majority of data available derive from preliminary phase I and II trials evaluating CTLA-4 and PD-1 as monotherapy or in combination with each other, vaccines, radiotherapy or targeted/hormonal therapy, achieving only limited benefits in terms of biochemical and radiologic responses. There are many reasons that may explain why prostate cancer responds poorly to modern immunotherapies, such as its characteristic low tumor mutational burden or immune-suppressive tumor microenvironment. The present review summarizes the results obtained treating advanced prostate cancer patients with immune-checkpoints inhibitors and analyzes potential mechanisms of both resistance and sensitivity, in order to hypothesize possible avenues of special interest for future research.     

Inhibition of Wnt/β-catenin pathway overcomes therapeutic resistance to abiraterone in castration-resistant prostate cancer

Abiraterone acetate has been clinically approved for the treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite improved survival outcomes with abiraterone, almost all patients develop therapeutic resistance and disease recurrence, progressing to a more aggressive and lethal phenotype. Bioinformatics analyses predicted activation of canonical Wnt/β-catenin and involvement of stem cell plasticity in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and β-catenin and their crosstalk causes activation of AR target genes and regulatory networks for which overcoming acquired resistance remains a major challenge. Here we show that co-treatment with abiraterone and ICG001, a β-catenin inhibitor, overcomes therapeutic resistance and significantly inhibited markers of stem cell and cellular proliferation in abiraterone-resistant prostate cancer cells. Importantly, this combined treatment abrogated the association between AR and β-catenin; diminished SOX9 expression from the complex more prominently in abiraterone-resistant cells. In addition, combined treatment inhibited tumor growth in an in vivo abiraterone-resistant xenograft model, blocked stemness, migration, invasion, and colony formation ability of cancer cells. This study opens new therapeutic opportunity for advanced-stage castration-resistant prostate cancer patients.     

Molecular aspects of prostate cancer with neuroendocrine differentiation

Neuroendocrine differentiation (NED), which is not uncommon in prostate cancer, is increases in prostate cancer after androgen-deprivation therapy (ADT) and generally appears in castration-resistant prostate cancer (CRPC). Neuroendocrine cells, which are found in normal prostate tissue, are a small subset of cells and have unique function in regulating the growth of prostate cells. Prostate cancer with NED includes different types of tumor, including focal NED, pure neuroendocrine tumor or mixed neuroendocrine-adenocarcinoma. Although more and more studies are carried out on NED in prostate cancer, the molecular components that are involved in NED are still poorly elucidated. We review neuroendocrine cells in normal prostate tissue, NED in prostate cancer, terminology of NED and biomarkers used for detecting NED in routine pathological practice. Some recently reported molecular components which drive NED in prostate cancer are listed in the review.     

Stanniocalcin 2 overexpression in castration-resistant prostate cancer and aggressive prostate cancer

Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy based on castration. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype where they progress aggressively and show very poor response to any anticancer therapies. To characterize the molecular features of these clinical castration-resistant prostate cancers, we previously analyzed gene expression profiles by genome-wide cDNA microarrays combined with microdissection and found dozens of trans -activated genes in clinical castration-resistant prostate cancers. Among them, we report the identification of a new biomarker, stanniocalcin 2, as an overexpressed gene in castration-resistant prostate cancer cells. Real-time polymerase chain reaction and immunohistochemical analysis confirmed overexpression of stanniocalcin 2, a 302-amino-acid glycoprotein hormone, specifically in castration-resistant prostate cancer cells and aggressive castration-naïve prostate cancers with high Gleason scores (8–10). The gene was not expressed in normal prostate, nor in most indolent castration-naïve prostate cancers. Knockdown of stanniocalcin 2 expression by short interfering RNA in a prostate cancer cell line resulted in drastic attenuation of prostate cancer cell growth. Concordantly, stanniocalcin 2 overexpression in a prostate cancer cell line promoted prostate cancer cell growth, indicating its oncogenic property. These findings suggest that stanniocalcin 2 could be involved in aggressive phenotyping of prostate cancers, including castration-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers. ( Cancer Sci 2009; 100: 914–919)     

前列腺癌放疗中前列腺体积缩小与新辅助内分泌治疗时间的关系研究

目的 探讨前列腺癌放疗中体积变化与新辅助内分泌治疗(NHT)之间的关系。方法 55例接受NHT前列腺癌患者连续入组,放疗中每周测量前列腺左右、上下、前后方向直径并计算体积。分析放疗中前列腺缩小与NHT时间、放疗前体积及前列腺癌风险分组间关系。结果 所有患者前列腺体积均随放疗进行而减小,NHT时间短者各项变化幅度大于时间长者。前列腺体积正常组与增大组比,前者在放疗7周后体积变化比例及各方向直径变化幅度均较大,且放疗前NHT时间较短,前列腺癌风险较低。与放疗前相比,中低危患者NHT≤4个月的体积分别缩小至68.10%、78.70%(P=0.002),而>4个月者变化较微弱;高危以上患者NHT≤6个月的体积分别缩小至76.59%及85.46%(P=0.001),而>6个月者相近。结论 NHT时间越长,放疗中前列腺体积及各方向直径变化幅度越小。中低危前列腺癌患者NHT4个月以后前列腺体积的变化幅度较小,高危或局部进展期患者NHT时间6个月以后变化幅度较小。     

p63 cytoplasmic aberrance is associated with high prostate cancer stem cell expression

Introduction: Prostate cancer in Indonesia is the 3rd ranking cancer among males and the 5th rank for theircancer mortality. Prognostic markers that can identify aggressive prostate cancer in early stages and helpselect appropriate therapy to finally reduce the mortality are therefore urgently needed. It has been suggestedthat stem cells in the prostate gland have a role in initiation, progression, and metastasis of cancer, althoughcontroversy continues to exist. Maintenance of normal stem cell or reserve cell populations in several epitheliaincluding prostate has been shown to be regulated by p63 and alteration of p63 expression is considered to havean oncogenic role in prostate cancer. We hypothesize that the expression of cytoplasmic aberrance of p63 isassociated with high ALDH1A1 expression as a cancer stem cell marker, thus leading to progression of prostatecancer. Methods: Using a cross-sectional study during two years (2009-2010), a total of 79 paraffin embeddedtissues of benign prostatic hyperplasia, PIN prostatic intraepithelial neoplasia, low and high Gleason scoreprostate cancer were investigated using immunohistochemistry. Associations between cytoplasmic p63 andALDH1A1, as well as with pathological diagnosis, were analyzed by Chi-Square test using SPSS 15.0. Links ofboth markers with cell proliferation rate (KI-67) and apoptotic rate (cleaved caspase 3) were also analyzed byKruskal-Wallis test. Results: The mean age of patient at the diagnosis is 70.0 years. Cytoplasmic aberrance ofp63 was associated with ALDH1A1 expression (p<0.001) and both were found to have significant relationshipswith pathological diagnosis (including Gleason score), (p=0.006 and p<0.001 respectively). Moreover, it was alsofound that higher levels of cytoplasmic p63 were significantly associated with the frequency of proliferatingcells and cells undergoing apoptosis in prostate cancers (p=0.001 and p=0.016 respectively). Conclusion: p63cytoplasmic aberrance is associated with high ALDH1A1 expression. These components are suggested to havean important role in prostate cancer progression and may be used as molecular markers.     

Prostate cancer stem cells: deciphering the origins and pathways involved in prostate tumorigenesis and aggression

The cells of the prostate gland are dependent on cell signaling pathways to regulate their growth, maintenance and function. However, perturbations in key signaling pathways, resulting in neoplastic transformation of cells in the prostate epithelium, are likely to generate subtypes of prostate cancer which may subsequently require different treatment regimes. Accumulating evidence supports multiple sources of stem cells in the prostate epithelium with distinct cellular origins for prostate tumorigenesis documented in animal models, while human prostate cancer stem-like cells (PCSCs) are typically enriched by cell culture, surface marker expression and functional activity assays. As future therapies will require a deeper understanding of its cellular origins as well as the pathways that drive PCSC maintenance and tumorigenesis, we review the molecular and functional evidence supporting dysregulation of PI3K/AKT, RAS/MAPK and STAT3 signaling in PCSCs, the development of castration resistance, and as a novel treatment approach for individual men with prostate cancer.     

Predicting patient-specific response to adaptive therapy in metastatic castration-resistant prostate cancer using prostate-specific antigen dynamics

Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.     

Androgen receptor-independent prostate cancer: an emerging clinical entity

Androgen deprivation therapy remains the backbone of prostate cancer treatment given its pivotal role in the pathogenesis of prostate cancer. The growing knowledge of androgen receptor-independent (i.e. AR-null) prostate cancer cells, however, might advance the treatment paradigm of prostate cancer. Here, we examined the results of two recent studies, published in Cancer Cell by Bluemn and Shukla et al., and their impact in the future management of castration-resistant prostate cancer.     

Primitive origins of prostate cancer: In vivo evidence for prostate‐regenerating cells and prostate cancer‐initiating cells

Tissue stem cells have been linked to cancers of epithelial origin including the prostate. There are three relevant issues concerning stem cells and cancer that rely solely on functional studies: 1. Are there tissue-regenerating stem cells in the adult organ? 2. Can tissue-regenerating cells serve as targets for transformation? 3. Do primary tumors contain tumor-propagating (cancer stem) cells? We will review the recent literature with respect to these critical issues to provide a direct link between primitive cells and prostate cancer.