ARV7 and ARFL mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 207-207
Author(s):  
Mercedes Marin ◽  
Natalia Jiménez ◽  
Òscar Reig ◽  
Maria Verónica Pereira ◽  
Maria Mila ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Mononuclear Cells ◽  
Specific Antigen ◽  
Post Treatment ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Peripheral Blood Mononuclear ◽  
Castration Resistant ◽  
Docetaxel Treatment

207 Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.

scholarly journals Androgen Receptor and Its Splicing Variant 7 Expression in Peripheral Blood Mononuclear Cells and in Circulating Tumor Cells in Metastatic Castration-Resistant Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 203 ◽  
Author(s):  
Mercedes Marín-Aguilera ◽  
Natalia Jiménez ◽  
Òscar Reig ◽  
Ruth Montalbo ◽  
Ajit K. Verma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Castration Resistant Prostate Cancer ◽  
Peripheral Blood Mononuclear ◽  
Splicing Variant ◽  
Castration Resistant ◽  
Blood Mononuclear Cells

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation.

scholarly journals Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

2021 ◽  
Author(s):  
Fred Saad ◽  
Martin Bögemann ◽  
Kazuhiro Suzuki ◽  
Neal Shore
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Imaging Techniques ◽  
Specific Antigen ◽  
Conventional Imaging ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Consensus Statements

Abstract Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required. Methods In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function. Results and conclusions While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

scholarly journals Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengfang Liu ◽  
Cheng Liu ◽  
Keqiang Yan ◽  
Jikai Liu ◽  
Zhiqing Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Protease ◽  
Hormone Sensitive

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

scholarly journals Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

2017 ◽  
Vol 35 (28) ◽  
pp. 3181-3188 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Scott T. Tagawa ◽  
Giuseppe Galletti ◽  
Daniel Worroll ◽  
Karla Ballman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Clinical Benefit ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Historical Control ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biomarker Analysis

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

scholarly journals Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012

2018 ◽  
Vol 36 (10) ◽  
pp. 991-999 ◽  
Author(s):  
Maha Hussain ◽  
Stephanie Daignault-Newton ◽  
Przemyslaw W. Twardowski ◽  
Costantine Albany ◽  
Mark N. Stein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Multivariable Analysis ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Exploratory Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biomarker Analysis ◽  
Repair Defect

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.

scholarly journals Novel Treatment Strategy Using Second-Generation Androgen Receptor Inhibitors for Non-Metastatic Castration-Resistant Prostate Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 661
Author(s):  
Doo Yong Chung ◽  
Jee Soo Ha ◽  
Kang Su Cho
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Second Generation ◽  
Randomized Clinical Trials ◽  
Specific Antigen ◽  
Significant Proportion ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Non-metastatic castration-resistant prostate cancer (nmCRPC) is defined by a progressively rising prostate-specific antigen level, despite a castrate level of testosterone, in the absence of obvious radiologic evidence of metastatic disease on conventional imaging modalities. As a significant proportion of patients with nmCRPC develop metastatic diseases, the therapeutic goals of physicians for these patients are to delay metastasis development, preserve quality of life, and increase overall survival (OS). Since 2018, the treatment of nmCRPC has changed dramatically with the introduction of second-generation androgen receptor inhibitors, such as enzalutamide (ENZA), apalutamide (APA), and darolutamide (DARO). These drugs demonstrated substantial improvements in metastasis-free survival (MFS) and OS in phase Ⅲ randomized clinical trials. In addition, these drugs have an excellent safety profile, preserve quality of life, and can delay disease-related symptoms. A recently published indirect meta-analysis reported that APA and ENZA showed better findings in MFS and that DARO had relatively fewer adverse effects. However, in the absence of a direct comparison, careful interpretation is required. Thus, APA, ENZA, and DARO should be considered the new standard drugs for treating nmCRPC.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Interacts with the Androgen Receptor (AR) and Promotes Prostate Cancer Cell Growth by Activating the AR

2010 ◽  
Vol 24 (1) ◽  
pp. 114-127 ◽  
Author(s):  
Masaki Shiota ◽  
Akira Yokomizo ◽  
Yasuhiro Tada ◽  
Junichi Inokuchi ◽  
Katsunori Tatsugami ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Target Genes ◽  
Specific Antigen ◽  
Peroxisome Proliferator ◽  
Castration Resistant Prostate Cancer ◽  
Promoter Regions ◽  
Peroxisome Proliferator Activated Receptor ◽  
Castration Resistant

Abstract There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was found to be an AR cofactor. PGC-1α interacted with the N-terminal domain of AR, was involved in the N- and C-terminal interaction of AR, and enhanced the DNA-binding ability of AR to androgen-responsive elements in the prostate-specific antigen enhancer and promoter regions to increase the transcription of AR target genes. Silencing of PGC-1α suppressed cell growth of AR-expressing prostate cancer (PCa) cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, PGC-1α knock-down also suppressed cell growth in the castration-resistant LNCaP-derivatives. These findings indicate that PGC-1α is involved in the proliferation of AR-expressing PCa cells by acting as an AR coactivator. Modulation of PGC-1α expression or function may offer a useful strategy for developing novel therapeutics for PCa, including CRPC, which depends on AR signaling by overexpressing AR and its coactivators.

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