Increased expression of androgen receptor (AR) and enzymes involved in androgen synthesis in metastatic prostate cancer: Targets for novel personalized therapies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
N. Mitsiades ◽  
N. Schultz ◽  
B. S. Taylor ◽  
H. Hieronymus ◽  
J. Satagopan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Androgen Receptor ◽  
Normal Tissue ◽  
Expression Profiles ◽  
Prostate Tissue ◽  
Steroidogenic Enzymes ◽  
Normal Prostate ◽  
Androgen Synthesis ◽  
Normal Prostate Tissue

5002 Background: Androgen receptor (AR) signaling remains active in castration-resistant prostate cancer (CRPC) despite castrate levels of circulating androgens. This is indicated by continuous expression of androgen-responsive genes and is due to mechanisms that include: increased AR expression; AR mutations allowing promiscuous activation by alternative ligands; and increased intratumoral androgen levels, resulting from in situ steroidogenesis. Methods: Gene expression profiles of 30 normal prostate tissue samples, 131 primary prostate carcinomas (PCas) and 16 metastatic PCas, generated using Affymetrix Exon arrays, were interrogated for levels of 40 mRNAs encoding AR, SHBG, 28 enzymes involved in androgen synthesis and 10 enzymes involved in androgen inactivation. For individual tumors, a transcript was considered to be overexpressed or underexpressed when its levels were >2 SDs higher or lower, respectively, than its average levels in normal tissue. Results: Metastatic PCas expressed higher average transcript levels for AR and several steroidogenic enzymes, including SRD5A1 and SRD5A3, than primary PCas and normal prostate tissue. Expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 mRNAs was decreased both in primary and metastatic tumors compared to normal prostate tissue. In analysis involving AR and 28 steroidogenic transcripts in individual tumors, all (16/16) metastatic PCas overexpressed at least one transcript (range: 2–14, median: 5 transcripts) compared to normal tissue, while 100/131 (76%) primary PCas overexpressed at least one transcript (range: 2–16, median: 2). Conclusions: Metastatic PCas overexpress AR and several steroidogenic enzymes, while they express lower levels of the androgen-inactivating enzymes CYP3A4, CYP3A5, and CYP3A7. These data highlight the role of AR and the androgen synthetic pathway as a therapeutic target in CRPC. Novel antiandrogens (MDV3100) and CYP17 inhibitors (abiraterone) are already in clinical trials in CRPC. Overexpression of AR or steroidogenic enzymes may serve as a biomarker (e.g. by detection via RT-PCR in circulating tumor cells) to predict for sensitivity to these agents and guide patient selection for participation in clinical trials. No significant financial relationships to disclose.

scholarly journals An expanded variant list and assembly annotation identifies multiple novel coding and noncoding genes for prostate cancer risk using a normal prostate tissue eQTL data set

PLoS ONE ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. e0214588
Author(s):  
Melissa S. DeRycke ◽  
Melissa C. Larson ◽  
Asha A. Nair ◽  
Shannon K. McDonnell ◽  
Amy J. French ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Prostate Cancer Risk ◽  
Prostate Tissue ◽  
Data Set ◽  
Normal Prostate ◽  
Normal Prostate Tissue ◽  
Eqtl Data

Use of nuclear androgen receptor status to predict early biochemical recurrence of prostate cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21073-21073
Author(s):  
J. Diallo ◽  
A. Aldejmah ◽  
M. Alam Fahmy ◽  
I. Koumakpayi ◽  
A. Mes-Masson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Early Onset ◽  
Biochemical Recurrence ◽  
Normal Tissue ◽  
Cellular Localization ◽  
Nuclear Staining ◽  
Normal Prostate ◽  
Kaplan Meier ◽  
Hormone Sensitive

21073 Background: Prostate cancer (PCa) is a leading cause of cancer death in North American men. The androgen receptor (AR) has an established role in the progression of this disease; however, it is unclear at what stage it intervenes. It is also uncertain whether the AR can be a useful prognostic marker for PCa. In this study, we assessed AR expression and sub-cellular localization in normal prostate as well as in androgen sensitive and insensitive PCa (AIPCa) tissues, and evaluated the ability of the AR to predict biochemical recurrence (BCR). Methods: We used tissue micro-arrays containing prostate tissue cores obtained from cancer-free patients (n=43), AIPCa patients (n=36), and patients with hormone-sensitive cancers (n=64) from which were collected both cancerous and normal adjacent tissue. Using immmunohistochemistry, we stained the tissue micro-arrays with a monoclonal antibody recognizing the AR. Two observers assessed the frequency and intensity of both cytoplasmic and nuclear AR staining. AR cytoplasmic (Ci) and nuclear (Ni) indices were calculated by multiplying nuclear staining frequency and nuclear staining intensity. Kaplan Meier, and Cox multivariate analyses were done using SPSS. Results: We found that AR Ci increased significantly in AIPCa although a modest but significant increase in PCa Ci was observed compared to normal tissues. In contrast, AR Ni was significantly lower in cancer-free patients as opposed to that seen in normal tissue adjacent to cancer. Similarly, cancerous tissue exhibited higher AR Ni than its adjacent normal tissue (p<0.05, Kruskal-Wallis). Kaplan Meier analyses revealed that low AR Ni was predictive of an early onset of BCR (before 3-years) in the sub-cohort of hormone-sensitive patients (LR=6.51, p=0.011). Futhermore, low AR Ni remained an independent predictor of early BCR in a Cox multivariate model controlling for age, pre-operative PSA, lymph node invasion, Gleason score and surgical margin status (HR=2.28, 95% CI=1.04 - 5, p<0.05). Conclusions: We conclude that increased nuclear AR activity could be a pre-malignant step in PCa progression whereas its role within cancer cells may be more complex, as low AR nuclear activity was associated with early onset of BCR. No significant financial relationships to disclose.

Differential gene expression in prostate tissue according to vasectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 298-298
Author(s):  
Kathryn M Wilson ◽  
Travis Gerke ◽  
Ericka Ebot ◽  
Jennifer A Sinnott ◽  
Jennifer R. Rider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Diagnosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Prostate Tissue ◽  
Gene Set Enrichment ◽  
Normal Prostate ◽  
Gene Sets ◽  
Normal Prostate Tissue

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.

scholarly journals Multispectral Photoacoustic Imaging of Prostate Cancer: Preliminary Ex-vivo Results

2013 ◽  
Vol 3 ◽  
pp. 41 ◽  
Author(s):  
Vikram S. Dogra ◽  
Bhargava K. Chinni ◽  
Keerthi S. Valluru ◽  
Jean V. Joseph ◽  
Ahmed Ghazi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Predictive Value ◽  
Ex Vivo ◽  
Prostate Tissue ◽  
Human Prostate ◽  
Normal Prostate ◽  
Mean Intensity ◽  
Preliminary Results ◽  
Normal Prostate Tissue ◽  
Malignant Prostate

Objective: The objective of this study is to validate if ex-vivo multispectral photoacoustic (PA) imaging can differentiate between malignant prostate tissue, benign prostatic hyperplasia (BPH), and normal human prostate tissue. Materials and Methods: Institutional Review Board's approval was obtained for this study. A total of 30 patients undergoing prostatectomy for biopsy-confirmed prostate cancer were included in this study with informed consent. Multispectral PA imaging was performed on surgically excised prostate tissue and chromophore images that represent optical absorption of deoxyhemoglobin (dHb), oxyhemoglobin (HbO2), lipid, and water were reconstructed. After the imaging procedure is completed, malignant prostate, BPH and normal prostate regions were marked by the genitourinary pathologist on histopathology slides and digital images of marked histopathology slides were obtained. The histopathology images were co-registered with chromophore images. Region of interest (ROI) corresponding to malignant prostate, BPH and normal prostate were defined on the chromophore images. Pixel values within each ROI were then averaged to determine mean intensities of dHb, HbO2, lipid, and water. Results: Our preliminary results show that there is statistically significant difference in mean intensity of dHb (P < 0.0001) and lipid (P = 0.0251) between malignant prostate and normal prostate tissue. There was difference in mean intensity of dHb (P < 0.0001) between malignant prostate and BPH. Sensitivity, specificity, positive predictive value, and negative predictive value of our imaging system were found to be 81.3%, 96.2%, 92.9% and 89.3% respectively. Conclusion: Our preliminary results of ex-vivo human prostate study suggest that multispectral PA imaging can differentiate between malignant prostate, BPH and normal prostate tissue.

Integrated-omics of MRI-visible and -invisible prostate cancer identifies molecular correlations with clinical outcome.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17506-e17506
Author(s):  
Eric Kim ◽  
Natalia Miheecheva ◽  
Akshaya Ramachandran ◽  
Yang Lyu ◽  
Ilia Galkin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cell Density ◽  
Malignant Cell ◽  
Prostate Tissue ◽  
Malignant Cells ◽  
Normal Prostate ◽  
Normal Prostate Tissue ◽  
Clinically Significant ◽  
Wasserstein Distances

e17506 Background: The inclusion of multiparametric MRI (mpMRI) to prostate cancer (PCa) diagnostics has increased the detection rate and has improved the prediction rate of clinically significant PCa. Yet, mpMRI has a false negative rate of 12.6%, missing 6-13% of clinically significant PCa. The mechanisms underlying MRI visibility are poorly understood; therefore, to probe the molecular and cellular underpinnings of PCa MRI visibility, we profiled tissue from Gleason score and clinically matched patients with MRI-visible and MRI-invisible PCa who underwent radical prostatectomy. Methods: MRI-invisible (n = 7) and MRI-visible (n = 8) PCa tumors were evaluated with multiplex immunofluorescence (MxIF; 14 markers) and were subjected to gene expression profiling using the HTG EdgeSeq Oncology Biomarker Panel (2,549 genes). Gene expression analysis was also performed using The Cancer Genome Atlas (TCGA), including normal prostate (n = 52) and PCa (n = 387) tissue. Analyses were performed using the BostonGene automated pipeline. Results: MpMRI-visible PCa tumors (62.5%) displayed compact epithelial tumor architecture compared with mpMRI-invisible PCa tumors (28.5%). mpMRI-visible PCa had higher malignant cell density (p = 0.04) and increased neighboring malignant cells (p = 0.07), correlating with MRI-visible PCa complex tumor architecture (r = 0.49 for neighboring malignant cells vs tumor cell density). Tumor stromal organization differences were determined by measuring Wasserstein distances between distributions, and mpMRI-invisible PCa stroma appeared more similar to normal tissue. The visible group exhibited lower expression of stroma-enriched genes such as filamin C (FLNC) (FDR < 0.1) and cellular adhesion-related genes (FDR < 0.4), with gene expression signatures markedly different compared to normal prostate tissue. Higher malignant cell density, neighboring malignant cells, and Wasserstein distances, and low FLNC expression – all mpMRI visibility characteristics – were associated with patient relapse (p = 0.02). Low stroma signature expression in the TCGA cohort correlated with inferior PCa PFS (p = 0.005). Conclusions: This is the first integrated multi-omics analysis of clinically matched mpMRI-visible and -invisible PCa. mpMRI-invisible tumors exhibited molecular, cellular, and structural characteristics more akin to normal prostate tissue, which may render them undetectable by imaging. A stroma-associated gene signature, a mpMRI-invisible tumor feature, correlated with better PCa clinical outcomes.

Magnetic resonance fingerprinting in prostate cancer before and after contrast enhancement

2021 ◽  
pp. 20210479
Author(s):  
Young Sub Lee ◽  
Moon Hyung Choi ◽  
Young Joon Lee ◽  
Dongyeob Han ◽  
Dong-Hyun Kim
Keyword(s):  
Prostate Cancer ◽  
Magnetic Resonance ◽  
Prostate Gland ◽  
Prostate Tissue ◽  
Normal Prostate ◽  
Adc Value ◽  
Contrast Enhanced ◽  
Normal Prostate Tissue ◽  
Adc Values ◽  
T1 And T2

Objectives: To assess the apparent diffusion coefficient (ADC) values and the T1 and T2 values derived from nonenhanced (NE) and contrast-enhanced (CE) magnetic resonance fingerprinting (MRF) in the prostate gland and to evaluate differences in values among prostate cancer, the normal peripheral zone (PZ) and the normal transition zone (TZ). Methods: Fifty-seven patients (median age, 73 years; range, 48–86) with prostate cancer who underwent multiparametric MRI including NE and CE MRF were included in this study. T1 and T2 values were extracted from NE and CE MRF, respectively. Five quantitative values (the ADC, NE T1, NE T2, CE T1 and CE T2 values) were measured in three areas: prostate cancer, PZ and TZ. We compared the values among the three areas and evaluated the differences between NE MRF and CE MRF values. Results: ADC values and MRF-derived values were significantly higher in PZ than prostate cancer or TZ (p < 0.001). TZ had a significantly lower CE T1 but significantly higher values of the other variables than prostate cancer (p < 0.001). The T1 values in all three areas and the T2 values in prostate cancer and TZ were significantly lower on CE MRF than on NE MRF (p < 0.001). Conclusions: Quantitative analysis of NE and CE MRI can be conducted by using the MRF technique. The ADC value and the T1 and T2 values from CE MRF and NE MRF were found to be significantly different between prostate cancer and normal prostate tissue. Advances in knowledge The T1 and T2 values from contrast-enhanced MR fingerprinting are significantly different between prostate cancer and normal prostate tissue.

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