Clinical development of novel therapeutics for castration-resistant prostate cancer: Historic challenges and recent successes

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration‐resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration‐resistant prostate cancer has undeniably accelerated the transition of novel approaches from “bench to bedside,” the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration‐resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration‐resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease. CA Cancer J Clin 2012;. © 2012 American Cancer Society.     

Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer

After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.     

Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer

Despite multiple advances in prostate cancer therapy, treatment options for castration resistant disease are very limited. While data from recent studies are encouraging, there is no drug that has significantly improved results of standard chemotherapy. Some of the most consistent results are provided by antiangiogenic agents, showing high response rates and manageable toxicity. We describe some of the main therapeutic angiogenesis inhibitors in metastatic castration resistant prostate cancer. These agents include vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, antiangiogenic and inmunomodulatory agents and endothelin receptor antagonists.     

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。     

Stepping-stones to the further advancement of androgen-deprivation therapy for prostate cancer

Androgen-deprivation therapy has remained the critical therapeutic option for patients with advanced prostate cancer for over 60 years. Patients with poorly differentiated prostate cancer have low dihydrotestosterone levels in the prostate. After androgen-deprivation therapy, dihydrotestosterone levels in the prostate remain at approximately 25% of the level measured before therapy. The addition of a nonsteroidal anti-androgen to luteinizing hormone-releasing hormone analog or surgical castration significantly reduces the risk of all causes of death by 8%, which translates into a small, but significant, improvement in the 5-year survival of 2.9% over castration alone. The biologically aggressive prostate cancer cells may have an androgen receptor with heightened sensitivity to low dihydrotestosterone levels from the early stage of androgen-dependent disease. It is necessary to consider the androgen environment and the status of the androgen receptor in the prostate in order to improve the clinical efficacy of androgen-deprivation therapy and the quality of life of patients.     

以肺转移癌为首发表现的前列腺癌长期存活1例报告并文献复习

目的:探讨转移性去势抵抗前列腺癌长期存活的特点及治疗方法。方法:对1例以肺转移为首发表现的前列腺癌长期存活病人的临床资料进行回顾性分析,并复习相关文献。结果:本例发现时即有肺转移的前列腺癌晚期病人,经过手术去势和间断的联合药物激素阻断治疗、化疗和新型抗前列腺癌药物阿比特龙等综合治疗,存活19年,且目前仍病情较平稳。结论:对于转移性前列腺癌应采取个体化的综合治疗,以期达到最佳的治疗效果。     

Efficacy of c-Met inhibitor for advanced prostate cancer

Background  

Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.     

Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice.

PURPOSE: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. EXPERIMENTAL DESIGN: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. RESULTS: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. CONCLUSION: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.     

Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness

A standard treatment for advanced prostate cancer is androgen deprivation by surgical or medical castration. In theory, however, combined androgen blockade (CAB) with an antiandrogen plus castration should be more effective because castration alone does not completely eliminate androgens in the prostate. Therefore, a number of randomized clinical trials (RCT) were conducted in the 1990s to investigate the efficacy of CAB with an antiandrogen (nilutamide or flutamide) plus castration; however, there were both positive and negative results for the efficacy of CAB. The lack of data on safety, quality of life (QOL) and cost-effectiveness has been a hindrance to the adoption of CAB for the treatment of prostate cancer. Nevertheless, discussion on CAB for the treatment of prostate cancer has continued for over 20 years, which suggests that there remains some hope for this regimen. In the 2000s, clinical research on CAB with the antiandrogen bicalutamide commenced. CAB using this new antiandrogen was found to prolong overall survival (OS) in patients with prostate cancer, with favorable safety profiles and cost-effectiveness, without deteriorating QOL. In this article, we discuss the feasibility of CAB with bicalutamide for the treatment of prostate cancer by reviewing the theoretical background of CAB and then the results of RCT conducted in the 1990s when the usefulness of CAB was assessed.     

Novel approaches and future directions in castration-resistant prostate cancer

Recent advances in the treatment of castration-resistant prostate cancer (CRPC) have started to change the therapeutic landscape allowing clinicians to choose from a broad range of treatment options. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state has enabled investigators to explore critical pathways involved in such process allowing for rational therapeutic design. These novel therapies complement the modest success that chemotherapy has demonstrated in recent years.In this review, we discuss the different mechanisms that render PCA castration resistant and elaborate on the nonchemotherapy approaches evolving in CRPC. These include agents targeting the epidermal growth factor receptor, endothelin receptor antagonists, angiogenesis inhibitors, immunomodulatory agents, immunotherapy, novel antiandrogens, and delivery of cytotoxic agents via therapeutic antibodies. This timely review coincides with the identification of newer therapies in this setting affirming our steady movement towards better disease control.     

Quo vadis: Advanced prostate cancer—clinical care and clinical research in the era of multiple androgen receptor‐directed therapies

The novel androgen receptor‐directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration‐resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor‐directed therapies, such as ARN‐509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable. Although advances in genomic technologies have led to unprecedented understanding of the biology of castration‐resistant prostate cancer, efforts only now are underway to elucidate the mechanisms of resistance associated with abiraterone and enzalutamide. A tremendous challenge in the near future will be to determine the optimal sequence or combination of therapies to overcome resistance mechanisms. In this review, the current landscape of androgen receptor‐directed therapies and future directions necessary to enhance their clinical efficacy for the maximal benefit of patients are discussed. Cancer 2015;121:361–371. © 2014 American Cancer Society.     

Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease

Nonmetastatic castration-resistant prostate cancer (nmCRPC) - defined as prostate-specific antigen (PSA) > 2 ng/mL, testosterone castration levels < 1.7 nm/L, and the absence of metastatic lesions on conventional imaging (computed tomography or bone scan) - has been defined as a lethal disease by the Prostate Cancer Work Group. One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC, with death occurring an average of 2.5 years after diagnosis of castration resistance. Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment. In patients with short PSA doubling times (< 10 mo) and high baseline PSA levels, there is a high risk of bone metastases followed by prostate cancer-related mortality. These patients also present significant morbidity that negatively impacts quality of life (QoL). Recently, the results of three randomized trials (PROSPER, SPARTAN, and ARAMIS) were published. Those trials evaluated the efficacy of three different androgen receptor inhibitors - enzalutamide, apalutamide, and darolutamide - in patients with nmCRPC. In all three trials, the study drugs improved both metastasis-free survival and overall survival compared to placebo, plus on-going androgen deprivation therapy without a negative impact on QoL. In patients with nmCRPC, the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval. For patients with nmCRPC, these novel drugs offer new hope for better QoL and survival outcomes.     

The Role of IMiDs Alone or in Combination in Prostate Cancer

Recent insights into mechanisms by which prostate cancer becomes castration resistant have allowed better and more rational therapeutic design. These novel therapies have complemented the modest success that chemotherapy has shown in recent years changing the landscape of this disease and leading to improved outcomes. Angiogenesis and immune deregulation are 2 pathways that have increasingly been shown to lead into castration resistant prostate cancer (CRPC). Thalidmide and lenalidomide are immunomodulatory agents with antiangiogenesis properties that have shown activity in this setting with acceptable safety profile. In this review, we discuss briefly the different mechanisms that render prostate cancer castration resistant and elaborate on thalidomide and lenalidomide data in CRPC after reviewing their theoretic mechanisms of action. This timely review coincides with the identification of newer therapies against CRPC affirming our steady movement toward better disease control.     

Radium-223 dichloride: a new paradigm in the treatment of prostate cancer

Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients’ profile that make them suitable to therapy and chances for further studies.     

手术去势间断联合多西他赛治疗晚期前列腺癌的疗效观察

目的：探讨手术去势间断联合多西他赛治疗晚期前列腺癌的临床疗效。方法收集75例转移性前列腺癌患者的病历资料。按照临床治疗方法不同将患者分为实验组和对照组,实验组28例,对照组47例。实验组患者采取睾丸切除去势＋多西他赛治疗,对照组患者采取睾丸切除去势治疗。观察患者的临床疗效、PSA水平、疼痛评分及不良反应发生情况,观察患者生活质量评分变化情况。结果实验组患者治疗后PSA水平、疼痛评分低于治疗前和对照组,差异有统计学意义（P＜0．05）;治疗后,对照组患者PSA水平、疼痛评分低于治疗前,差异有统计学意义（P＜0．05）。实验组患者红细胞、白细胞减少,恶心呕吐,骨髓抑制,手足综合征,脱发发生率显著低于对照组,差异有统计学意义（P＜0．05）。实验组患者生活质量评分高于治疗前和对照组,差异有统计学意义（P＜0．05）;治疗后,对照组患者生活质量评分高于治疗前,差异有统计学意义（ P＜0．05）。实验组患者中位生存时间、无进展生存时间、2年生存率均高于对照组,差异有统计学意义（P＜0．05）。结论手术去势间断联合多西他赛治疗晚期前列腺癌效果较好,能改善患者PSA水平、疼痛情况,减少不良反应发生情况,提高患者的生活质量,临床应用价值较高。     

First line therapy in the treatment of metastatic prostate cancer

Hormonal therapy has been the main treatment for advanced prostate cancer for the past six decades. Maximum androgen blockade (MAB), combination therapy with castration and antiandrogens, has been compared with castration monotherapy since the late 1980s. However, the results of the different trials have been conflicting. Recently published meta-analyses have revealed that MAB with non-steroidal antiandrogens is slightly superior to monotherapy (surgical or medical castration) in the treatment of advanced prostate cancer, and that MAB has more adverse effects. The question of whether the modest survival advantage of MAB balances with the increase in adverse effects should be investigated. Some studies indicated that the survival of metastatic prostate cancer patients treated with immediate therapy was similar to that of men in whom treatment was delayed. Hormonal therapy has side effects and is costly, and delayed treatment may be beneficial to elderly men with silent metastasis. Intermittent hormonal therapy is a controversial approach to management of advanced prostate cancer, although laboratory data suggest that intermittent androgen deprivation may prolong the duration of androgen dependence. Intermittent hormonal therapy for patients with metastatic prostate cancer needs to be assessed in a randomized trial to determine the effect on overall survival and quality of life. Our results in a randomized clinical trial of chemo-endocrine therapy versus endocrine therapy alone suggested that the addition of chemotherapy (cisplatin plus pirarubicin) to initial endocrine therapy might be beneficial to patients with advanced prostate cancer, especially an aggressive form of prostate cancer. However, chemo-endocrine therapy should be considered an experimental approach at present.     

CCL2 induces resistance to the antiproliferative effect of cabazitaxel in prostate cancer cells

Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel‐resistant and castration‐resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C‐C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel‐resistant cell line, DU145‐TxR/CxR, from a previously established paclitaxel‐resistant cell line, DU145‐TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145‐TxR and DU145‐TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145‐TxR and DU145‐TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145‐TxR and DU145‐TxR/CxR cells under treatments of cabazitaxel. The CCL2‐CCR2 axis decreased apoptosis through the inhibition of caspase‐3 and poly(ADP‐ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2‐CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel.