Role of the novel generation of androgen receptor pathway targeted agents in the management of castration-resistant prostate cancer: A literature based meta-analysis of randomized trials

Roviello, Giandomenico; Sigala, Sandra; Sandhu, Shahneen; Bonetta, Alberto; Cappelletti, Maria Rosa; Zanotti, Laura; Bottini, Alberto; Sternberg, Cora N.; Fox, Stephen B.; Generali, Daniele

doi:10.1016/j.ejca.2016.04.002

Cited by 52 publications

(56 citation statements)

References 39 publications

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“…13,16 It should be noted that the last patients to be included in the 5-year mortality analyses were diagnosed in 2008 and 2009, respectively; and although, some might have benefitted from secondline chemotherapy, very few have received novel, lifeprolonging treatment regimens such as abiraterone, enzalutamide, and early chemotherapy. 12,14,15 In the SEER data, a significant reduction in the incidence of de novo metastatic PCa was observed from 1995 onward ( Fig. 1, Table 2).…”

Section: Discussionmentioning

confidence: 93%

“…Concurrent with the dramatic changes in the incidence of PCa, life-prolonging treatment options for men with metastatic and castrationresistant PCa have been introduced. 12,13 Moreover, an optimized use of androgen-deprivation therapy and chemotherapy, better palliation, and improved management of comorbidities must be expected to improve the survival of contemporary men diagnosed with de novo metastatic PCa compared with their historic counterparts. [14][15][16] To investigate the impact of changes in early detection strategies and improved PCa care on incidence and mortality in men with de novo metastatic PCa, we analyzed data in 2 population-based cohorts from Denmark and the United States.…”

Section: Introductionmentioning

confidence: 99%

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Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—A population‐based analysis of 2 national cohorts

Helgstrand

Røder

Klemann

et al. 2018

Cancer

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Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—A population‐based analysis of 2 national cohorts

Helgstrand

Røder

Klemann

et al. 2018

Cancer

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“…All of these findings highlight the importance of further investigating EPHA3 expression and the related mechanism in PCa. PCa is the second most common carcinoma and the fifth leading cause of cancer-related deaths in men worldwide (28), in which the androgen receptor (AR) plays a pivotal role in the initiation and progression of PCa (29)(30)(31). The regulation of EPHA3 in PCa remains mostly unclear, and particularly the association between AR and EPHA3 regulation has been less studied.…”

Section: Androgen Receptor Induces Epha3 Expression By Interacting Wimentioning

confidence: 99%

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Xiao-wei

Chen

et al. 2018

Oncol Rep

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Erythropoietin‑producing hepatocellular carcinoma cell surface type‑A receptor 3 (EPHA3) has been found to promote the proliferation and survival of prostate cancer (PCa) cell lines and prostate tumor development in nude mice. However, the regulation of EPHA3 in PCa remains largely unknown. This study is aimed to investigate the association between EPHA3 expression and androgen receptor (AR) signaling and the potential mechanism. We determined mRNA and protein levels of EPHA3 and AR signaling‑related genes in the PCa cell line 22Rv1 by reverse transcription‑polymerase chain reaction (RT‑PCR) and western blotting, respectively. The EPHA3 mRNA and protein levels were both found to be elevated by dihydrotestosterone (DHT) hormone in a dose‑ and time‑dependent manner, as AR and prostate‑specific antigen (PSA) expression were increased. Similarly, EPHA3 protein levels were also increased in the PCa cell line LNCaP stimulated with DHT or mibolerone (Mib). Overexpression of pEGFP‑AR in 22Rv1 cells significantly increased the EphA3 level, while AR knockdown with small interfering RNA (siRNA) for AR (siAR) markedly decreased the expression of EPHA3. The key EPHA3 promoter region associated with AR regulation was evaluated by co‑transfection of various pGL3‑basic‑luciferase reporter plasmids, containing EPHA3 core promoter fragments differing in length, with the AR plasmid or siAR into 22Rv1 cells. AR overexpression in 22Rvl cells raised the EphA3 promoter transcription activity of pGL3‑EPHA3‑Luc (EPHA3‑Luc)‑789, and vice versa. Similarly, luciferase activity of EPHA3‑Luc‑317 was also clearly affected. However, truncated EPHA3‑Luc‑237 without the transcription factor specific protein 1 (SP1) binding sites or EPHA3‑Luc‑789ΔSP1 with modified SP1 binding sites clearly decreased EPHA3 promoter activity regardless of whether AR was overexpressed or blocked. Treatment of 22Rv1 cells with 10 and 100 nM of the SP1 inhibitor mithramycin A for 24 and 48 h significantly reduced EPHA3 mRNA and protein levels. Additionally, selective inhibition of SP1 with siRNA SP1 (siSP1) at various concentration from 25 to 75 nM, reduced the EPHA3 protein level in PCa LNCaP cells, accordingly. Co‑immunoprecipitation (co‑IP) and chromatin IP (ChIP) assays were performed to determine whether AR forms a transcription factor complex with Sp1 that binds the EPHA3 core promoter region to sense androgen induction. The result suggests that the interaction of AR and SP1 contributes to regulate EPHA3 expression, and the SP1 binding sites (‑295~‑261) in the EPHA3 core promoter region is crucial to the regulation of EPHA3 expression in response to androgen hormone stimuli.

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“…CRPC is defined by consecutive rises in serum prostate specific antigen (PSA) levels or/and progression of metastatic spread in the setting of castrate levels of testosterone [4, 5]. Despite recent advances in the treatment of patients progressing with metastatic CRPC, average survival remains approximately three years [6]. Identification of more effective and/or precise therapeutic approaches is a clinical unmet need.…”

Section: Introductionmentioning

confidence: 99%

Emerging Variants of Castration-Resistant Prostate Cancer

2017

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Metastatic castration resistant prostate cancer (CRPC) is associated with substantial clinical, pathologic, and molecular heterogeneity. Most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications for patient selection for AR-directed approaches. However, histologic and clinical resistance phenotypes can emerge after AR-inhibition, in which the tumors become less dependent on the AR. In this review we discuss prostate cancer variants including neuroendocrine (NEPC) and aggressive variant (AVPC) prostate cancers and their clinical implications. Improvements in the understanding of the biologic mechanisms and molecular features underlying prostate cancer variants may help prognostication and facilitate the development of novel therapeutic approaches for subclasses of patient with CRPC.

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Role of the novel generation of androgen receptor pathway targeted agents in the management of castration-resistant prostate cancer: A literature based meta-analysis of randomized trials

Cited by 52 publications

References 39 publications

Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—A population‐based analysis of 2 national cohorts

Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—A population‐based analysis of 2 national cohorts

Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1

Emerging Variants of Castration-Resistant Prostate Cancer

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