scholarly journals MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
C. Kalogirou ◽  
J. Linxweiler ◽  
P. Schmucker ◽  
M. T. Snaebjornsson ◽  
W. Schmitz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Competitive Inhibition ◽  
Cholesterol Biosynthesis ◽  
Strong Dependence ◽  
Specific Antigen ◽  
Micro Rna ◽  
Squalene Epoxidase ◽  
Cholesterol Biosynthesis Pathway ◽  
Pathway Inhibition

AbstractProstate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

scholarly journals Local and systemic morbidities of de novo metastatic prostate cancer in Singapore: insight from 685 consecutive patients from a large prospective Uro-oncology registry

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034331 ◽  
Author(s):  
Yu Guang Tan ◽  
Leonard Pang ◽  
Farhan Khalid ◽  
Randy Poon ◽  
Hong Hong Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Metastatic Prostate Cancer ◽  
Group Performance ◽  
De Novo ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
High Volume ◽  
Secondary Outcome ◽  
Systemic Complications

ObjectiveTo evaluate the incidence and management of local and systemic complications afflicting patients with de novo metastatic prostate cancer (mPCa) in Singapore.DesignRetrospective analysis of a large prospective Uro-oncology registry of mPCa.SettingThis study is carried out in a tertiary hospital in Singapore.ParticipantsWe reviewed our institution’s prospectively maintained database of 685 patients with mPCa over a 20-year period (1995–2014). Patients with non-mPCa or those progressed to metastatic disease after previous curative local treatments were excluded.Primary and secondary outcome measuresThe primary outcome was to evaluate the systemic and local morbidity rates associated with mPCa. Local complication was defined as the need for palliative procedures to relieve urinary obstruction, worsening renal function or refractory haematuria, while systemic complication was related to radiographic evidence of skeletal-related pathological fractures. Secondary outcomes analysed were the management and overall survival patterns over 20 years.Results237 (34.6%) patients required local palliative treatments. 88 (12.8%) patients presented with acute urinary retention, 23 patients (9.7%) required repetitive local palliative treatments. On multivariate analyses, prostate-specific antigen >100 (p=0.02) and prostate volume >50 g (p=0.03) were independent prognostic factors for significant obstruction requiring palliative procedures. 118 (17.2%) patients developed skeletal fractures, with poor Eastern Cooperative Oncology Group Performance (ECOG) status (p=0.01) and high volume bone metastasis (p<0.01) independently predictive of skeletal fractures. Altogether, 653 (95.3%) patients received androgen deprivation therapy (ADT), with the median time to castrate resistance of 21.4 months (IQR 7–27). The median overall survival was 45 months (IQR 20–63), with prostate cancer mortality of 81.4%. Improved overall survival was observed from 41.6 months (1995–1999) to 47.8 months (2010–2014) (p<0.01).ConclusionMorbidities and complications arising from mPCa are more common and debilitating than we thought, often requiring immediate palliative treatments, while many necessitate repeated interventions with progression.

Impact of the USPSTF recommendations on prostate cancer stage migration and de-novo metastatic prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 166-166 ◽  
Author(s):  
Yu-Wei Chen ◽  
Ruby Gupta ◽  
Moshe Chaim Ornstein ◽  
Brian I. Rini ◽  
Timothy D. Gilligan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
De Novo ◽  
Task Force ◽  
Specific Antigen ◽  
P Value ◽  
Stage Migration ◽  
Nodal Disease ◽  
Psa Screening ◽  
The Impact

166 Background: The US Preventive Services Task Force (USPSTF) recommended against prostate specific antigen (PSA) screening for men aged≥75 in 2008 and all men in 2012 in an effort to reduce overdiagnosis and overtreatment of men with prostate cancer (PCa). This recommendation may delay diagnosis of clinically significant PCa. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was used to identify men diagnosed with PCa between 2004-2015. PCa stage was categorized as localized (N0M0), nodal (N1M0) and metastatic (NxM1). Trend analysis was stratified on age group (PSA screening eligible was defined as age 55-69 according to the 2018 updated USPSTF recommendation). Multivariable logistic regression was used to identify predictors for nodal and metastatic disease. Results: Between 2004-2015, there were 603,323 men with PCa identified. Metastatic disease accounted for 2.8% of PCa in 2004-2008, 3.7% in 2009-2012, and 6.1% in 2013-2015. In men eligible for PCa screening, metastatic disease increased from 1.9% in 2004-2008, to 2.6% in 2009-2012, to 4.2% in 2013-2015; nodal disease increased from 1.4% to 1.6% to 2.6%, respectively (both p-value for trend< 0.0001). This stage migration was also observed in non-screening eligible groups (age >70 and <55). Compared with PCa diagnosed in 2009-2012, PCa diagnosed in 2013-2015 had higher odds of metastatic disease (AOR: 1.70, p-value<0.0001) or nodal disease (AOR: 1.71, p-value<0.0001). Conclusions: Men diagnosed with PCa in 2013-2015 were more likely to have metastatic or nodal disease, suggesting PCa stage migration since PSA screening was recommended to be discontinued in 2012. Although the impact of PSA screening on PCa mortality remains debatable, the reduced quality of life with advanced Pca should not be overlooked. Future population studies are warranted to investigate the influence of the updated 2018 USPSTF recommendation. [Table: see text]

Genetic variants in the cholesterol biosynthesis pathway genes and risk of prostate cancer

Gene ◽  
2021 ◽  
Vol 774 ◽  
pp. 145432
Author(s):  
Yifei Cheng ◽  
Yixuan Meng ◽  
Shuwei Li ◽  
Dongliang Cao ◽  
Shuai Ben ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Variants ◽  
Cholesterol Biosynthesis ◽  
Biosynthesis Pathway ◽  
Cholesterol Biosynthesis Pathway

Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone-metastatic prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 336-336
Author(s):  
Jinge Zhao ◽  
Guangxi Sun ◽  
Banghua Liao ◽  
Xingming Zhang ◽  
Pengfei Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Predictive Models ◽  
Metastatic Prostate Cancer ◽  
De Novo ◽  
Specific Antigen ◽  
Classification Systems ◽  
Castration Resistant Prostate Cancer ◽  
Final Model ◽  
Predictive Parameters ◽  
Castration Resistant

336 Background: Treatments for de novo metastatic prostate cancer (mPCa) are evolving. However predictive models for this subset of the population are still lacking. The aim of this study is to develop nomograms to predict the incidence of castration resistant PCa (CRPC) and overall survival (OS) for de novo mPCa patients. Methods: Data from 449 de novo mPCa patients were retrospectively analyzed. Patients were randomly divided into either the training or the validation cohort. Predictive factors were selected by Cox-proportional model and further used for building predictive models. The outcomes were incidence of CRPC and OS. Results: Predictive parameters included: Gleason Score (GS), intraductal carcinoma of the prostate (IDC-P), ECOG status, alkaline phosphatase (ALP), hemoglobin (HGB) and prostate specific antigen (PSA). IDC-P and GS were the strongest prognosticators for both the incidence of CRPC and OS. Nomograms for predicting CRPC and OS had an internal validated C-index of 0.762 and 0.723, respectively. Based on the beta-coefficients of the final model, risk classification systems were constructed. For those with favorable-, intermediate- and poor-prognosis, the median time to CRPC was 62.6, 28.0 and 13.0 months (P<0.001), and the median OS was not reached, 55.0 and 33.0 months, respectively (P<0.001). Conclusions: We developed two novel nomograms to predict the incidence of CRPC and OS for de novo mPCa patients. These tools may assist physicians’ decision-making and design of clinical trials.

scholarly journals Prostate-Specific antigen value and micro RNAs as potential diagnostic biomarkers for prostate cancer

2021 ◽  
Vol 8 (2) ◽  
pp. 107-113
Author(s):  
Aydemir Asdemir ◽  
Sevgi Durna Dastan ◽  
Esat Korgali ◽  
Tugba Yildiz Asdemir ◽  
Huseyin Saygin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Diagnostic Value ◽  
Micro Rna ◽  
Control Group ◽  
Diagnostic Biomarkers ◽  
Expression Levels ◽  
Non Invasive ◽  
Cancer Group ◽  
Micro Rnas

Objective: It is necessary to provide PSA alternatives or methods that can be used in conjunction with PSA to regress complications rising from negative biopsies and to increase diagnostic value. Patients and Methods: The study is consisting of 59 men as the sample group. Blood samples from the individuals are grouped as prostate cancer and BPH (benign prostatic hyperplasia) groups. 27 prostate cancer patients whom some of them also operated are assembled in the patients group and the other 32 individuals are grouped as BPH group. Micro RNA expression levels evaluated by RT-PCR. Results: Prostate cancer group when compared with the control group, it is observed that expression levels of miRNA-221 and miRNA-432 increased while expression levels of miRNA-17-5p, miRNA-30c, miRNA-107, miRNA-141, miRNA-145, miRNA-181a-2, miRNA-331-3p, miRNA-574-3p decreased and expression levels of miRNA-21 and miRNA-375 are quite similar between the groups. Conclusion: The prospect of strong and sensitive serum miRNA expression levels in prostate cancer cases which are easily detectable by non-invasive methods as biomarkers is a promising field of study. Nevertheless, it is currently necessary to work in conjunction with both tissue and serum to enhance both sensitivity and specificity of miRNAs as biomarkers. As such, expression levels of the same miRNAs in tissue and serum provide different expression values which in turn make it difficult to indicate a common biomarker.

scholarly journals Comparing the Survival Outcomes of Radical Prostatectomy Versus Radiotherapy for Patients With De Novo Metastasis Prostate Cancer: A Population-Based Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoxiao Guo ◽  
Haoran Xia ◽  
Xiaonan Su ◽  
Huiming Hou ◽  
Qiuzi Zhong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Primary Tumor ◽  
Comparative Effectiveness ◽  
De Novo ◽  
Specific Antigen ◽  
Cox Proportional Hazards ◽  
Survival Outcomes ◽  
Standardized Mortality Ratio ◽  
The Impact

PurposeThe efficacy of local treatments (LTs) in selected patients with metastatic prostate cancer (mPCa) had been demonstrated. However, the comparative effectiveness between LTs is unclear. Here, we compared the impact of radical prostatectomy (RP) and brachytherapy (RT) on the survival outcomes of mPCa patients.Materials and MethodsmPCa patients who received RT or RP between 2004 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable Cox proportional hazards analysis was used to evaluate the comparative risk of prostate cancer-specific mortality (CSM) and all-cause mortality (ACM) between LTs. A 1:1 propensity score matching (PSM) and adjusted standardized mortality ratio weighting (SMRW) were performed to balance the clinicopathological characteristics of the groups.ResultsOf 684 mPCa patients, 481 underwent RP and 203 received RT. After PSM, both groups included 148 cases, and RT resulted in comparable CSM versus RP [CSM: hazard ratio (HR) = 0.77, p = 0.325; ACM: HR = 0.73, p = 0.138], which was consistent with the SMRW model [CSM: HR = 0.83, p = 0.138; overall survival (OS): HR = 0.75, p = 0.132]. However, RP was associated with a lower CSM in the T1–2 subgroup (HR = 0.42, p = 0.048) and a lower ACM in the T1–2 (HR = 0.55, p = 0.031) and prostate-specific antigen (PSA) ≤20ng/ml (HR = 0.48, p = 0.022) subgroups. Besides, the results showed that the mortality risk was similar between the two groups in the T3–4, Gleason score (GS) &gt;7, PSA &gt;20 ng/ml, and all metastatic subgroups (all p &gt; 0.100).ConclusionsRP could confer better survival outcomes than could RT in mPCa patients with favorable primary tumor features, but not in those with advanced primary tumor features. Moreover, the metastatic substage has limited impact on the comparative effectiveness between RP and RT. Further clinical trials are necessary to confirm the present results.

scholarly journals Evaluation of micro-RNA in extracellular vesicles from blood of patients with prostate cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0262017
Author(s):  
Jiyoon Kim ◽  
Siwoo Cho ◽  
Yonghyun Park ◽  
Jiyoul Lee ◽  
Jaesung Park
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Extracellular Vesicles ◽  
Specific Antigen ◽  
Rna Isolation ◽  
Micro Rna ◽  
Control Group ◽  
Micro Rnas ◽  
The Mean ◽  
Better Than

Extracellular vesicles (EVs) contain various types of molecules including micro-RNAs, so isolating EVs can be an effective way to analyze and diagnose diseases. A lot of micro-RNAs have been known in relation to prostate cancer (PCa), and we evaluate miR-21, miR-141, and miR-221 in EVs and compare them with prostate-specific antigen (PSA). EVs were isolated from plasma of 38 patients with prostate cancer and 8 patients with benign prostatic hyperplasia (BPH), using a method that showed the highest recovery of RNA. Isolation of EVs concentrated micro-RNAs, reducing the cycle threshold (Ct) value of RT-qPCR amplification of micro-RNA such as miR-16 by 5.12 and miR-191 by 4.65, compared to the values before EV isolation. Normalization of target micro-RNAs was done using miR-191. For miR-221, the mean expression level of patients with localized PCa was significantly higher than that of the control group, having 33.45 times higher expression than the control group (p < 0.01). Area under curve (AUC) between BPH and PCa for miR-221 was 0.98 (p < 0.0001), which was better than AUC for prostate-specific antigen (PSA) level in serum for the same patients. The levels of miR-21 and miR-141 in EVs did not show significant changes in patients with PCa compared to the control group in this study. This study suggests isolating EVs can be a helpful approach in analyzing micro-RNAs with regard to disease.

Use and outcomes in men with metastatic castration-sensitive prostate cancer (mCSPC) treated with docetaxel in addition to androgen deprivation therapy (ADT): Analysis of real-world data in the United States (US).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19322-e19322
Author(s):  
Neeraj Agarwal ◽  
Suneel Mundle ◽  
Lindsay Dearden ◽  
Ravi C. Potluri ◽  
Sandhya Nair ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Real World ◽  
De Novo ◽  
Specific Antigen ◽  
The United States ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
The Real ◽  
The Us

e19322 Background: mCSPC patients treated with docetaxel + androgen deprivation therapy (D+ADT) demonstrate increased overall survival (OS)1,2. However, limited real-world outcome data is available for such patients. This study assesses the real-world use and outcomes with D+ADT in mCSPC in the US. Methods: Adult (≥18 years old) men with mCSPC (defined as men with metastasis at index diagnosis of prostate cancer [de novo] or those who progressed to mCSPC after prior diagnosis of localized disease) were retrospectively identified from the Optum (2007–2018) and SEER Medicare (2007–2016) databases. Men diagnosed with mCSPC in or after 2014 with exposure to docetaxel and no brain metastasis were included for analysis. Patients were characterized based on age; baseline prostate specific antigen (PSA) level; administration of ADT; prior radiotherapy (RT); prior radical prostatectomy (RP); presence of visceral disease, bone or bone + visceral metastases; and treatment duration of docetaxel. OS and time to metastatic castration-resistant prostate cancer (mCRPC) were measured. Results: Among 4959 men identified with mCSPC during or after 2014, 192 (3.8%) received D+ADT ± Bicalutamide as first line systemic therapy. Baseline characteristics are presented in the Table below. Mean ± SD duration of docetaxel exposure was 115 ± 84.2 days (median 118 days). Median OS among these men was 30.5 (28.1, 36.7) months and median time to mCRPC was 18.3 (14.5, 24.6) months. Only 9% of men received docetaxel for ≥6 cycles (180 days); median OS in these men was NR (19.1- NR) with 74% surviving at 2 years compared to 65% surviving at 2 years in those with docetaxel duration <6 cycles. Conclusions: Use of docetaxel in the real-world mCSPC patient population in the US is limited. Majority of men received less than the recommended dose of 6 cycles. OS with D+ADT in real-world patients with mCSPC appears to be lower than the OS reported in published trials. References:1) Sweeney CJ, et al. N Engl J Med. 2015;373:737–46. 2) James ND, et al. Lancet. 2016;387:1163–77. Funding: Janssen Research & Development, LLC. [Table: see text]

Approach to Oligometastatic Prostate Cancer

2016 ◽  
pp. 119-129 ◽  
Author(s):  
Brandon Bernard ◽  
Boris Gershman ◽  
R. Jeffrey Karnes ◽  
Christopher J. Sweeney ◽  
Neha Vapiwala
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Systemic Therapy ◽  
De Novo ◽  
Locally Advanced ◽  
Specific Antigen ◽  
Clinical State ◽  
Therapeutic Implications ◽  
Oligometastatic Prostate Cancer ◽  
Disease Free

Oligometastatic prostate cancer has increasingly been recognized as a unique clinical state with therapeutic implications. It has been proposed that patients with oligometastases may have a more indolent course and that outcome may be further improved with metastasis-directed local ablative therapy. In addition, there are differing schools of thoughts regarding whether oligometastases represent isolated lesions—where targeted therapy may render a patient disease free—or whether they coexist with micrometastases, where targeted therapy in addition to systemic therapy is required for maximal clinical impact. As such, the approach to the patient with oligometastatic prostate cancer requires multidisciplinary consideration, with surgery, radiotherapy, and systemic therapy potentially of benefit either singularly or in combination. Indeed, mounting evidence suggests durable disease-free intervals and, in some cases, possibly cure, may be achieved with such a multimodal strategy. However, selecting patients that may benefit most from treatment of oligometastases is an ongoing challenge. Moreover, with the advent of new, highly sensitive imaging technologies, the spectrum based on CT of the abdomen and pelvis and technetium bone scan of localized to oligometastatic to widespread disease has become increasingly blurred. As such, new MRI- and PET-based modalities require validation. As some clinical guidelines advise against routine prostate-specific antigen screening, the possibility of more men presenting with locally advanced or de novo oligometastatic prostate cancer exists; thus, knowing how best to treat these patients may become more relevant at a population level. Ultimately, the arrival of prospective clinical data and better understanding of biology will hopefully further inform how best to treat men with this disease.

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