scholarly journals NIMG-30. PET IMAGING OF ANDROGEN RECEPTOR EXPRESSION IN PATIENTS WITH GBM USING [18F]-FDHT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii154-ii154
Author(s):  
Anat Mordechai ◽  
Ofer Shamni ◽  
Nomi Zalcman ◽  
Samuel Moscovici ◽  
Alexandre Chicheportiche ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Protein Expression ◽  
Pearson Correlation ◽  
Receptor Expression ◽  
Whole Body ◽  
Normal Brain ◽  
Poor Overall Survival ◽  
Reference Tissue ◽  
Pet Ct ◽  
Tumor Accumulation

Abstract BACKGROUND GBM is associated with poor overall survival partly due to lack of effective treatment. Recently we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and that AR antagonists induced dose-dependent death in several glioblastoma cell lines. Treatment of mice implanted with human GBM with AR antagonists significantly reduced the growth of the tumor and prolonged the lifespan of the mice. 18f-fluorine-radiolabeled Dihidrotestosteron (DHT), a natural ligand of AR, [16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT)] is one of the PET tracers used to detect AR expression in metastatic prostate cancer. The aim of this study was to identify AR-expressing GBM tumors in real time using PET-CT scan with [18F]-FDHT. MATERIALS AND METHODS Twelve patients with GBM underwent a dynamic (first 30 min) and whole body static (later 60-80 min) [18F]-FDHT PET/CT (296-370 MBq) scans 2-4 days prior to the surgery or biopsy. Protein was extracted from the tumor and subjected to western blot analysis. AR Protein fold change of each tumor sample was calculated by densitometry analysis compared with that of normal brain, following normalization to GAPDH. RESULTS At ~60 min after injection, 6 of the 12 patients showed significantly higher tumor accumulation of [18F]-FDHT, compared to reference tissue (SUV/Control)mean: 1.33-2.63 fold, (SUV/control)max: 1.4-3.43 fold. The patient who had higher tumor accumulation of [18F]-FDHT, demonstrated also high (1.6-2.27 fold/normal brain) AR protein expression within the tumor. Pearson-correlation-coefficient analysis for the (SUV/Control)mean at ~60 min after the injection versus AR protein expression, was positive and significant (R=0.841;p=0.0024). CONCLUSION This study demonstrated for the first time that [18F]-FDHT PET can identify AR-positive-GBM-tumors (with sensitivity and specificity at 100%) and may therefore be a powerful tool to select patients eligible for treatment with AR antagonists. It could possibly be employed also to monitor treatment response and/or progression during the course of therapy.

scholarly journals [ 18F]-FDHT PET/CT as a Tool for Imaging Androgen Receptor Expression in High-Grade Glioma

2021 ◽  
Author(s):  
Marina Orevi ◽  
Ofer Shamni ◽  
Nomi Zalcman ◽  
Alexandre Chicheportiche ◽  
Anat Mordechai ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Protein Expression ◽  
Pearson Correlation ◽  
High Grade Glioma ◽  
Receptor Expression ◽  
Normal Brain ◽  
High Grade ◽  
Pet Tracer ◽  
Standardized Uptake Values ◽  
Pet Ct

Abstract Background Glioblastoma (GBM) is associated with poor overall survival. Recently, we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and AR antagonists induced dose-dependent death in several GBM cell lines and significantly reduced tumor growth and prolonged the lifespan of mice implanted with human GBM. 16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT) is a PET tracer used to detect AR expression in prostate and breast cancers. This study was aimed at exploring the ability of [18F]-FDHT-PET to detect AR expression in high-grade gliomas. Methods Twelve patients with suspected high-grade glioma underwent a regular workup and additional dynamic and static [ 18 F]-FDHT-PET/CT. Visual and quantitative analyses of [ 18 F]-FDHT kinetics in the tumor and normal brain were performed. Mean and maximum (max) standardized uptake values (SUVs) were determined in selected volumes of interest. The patients had surgery or biopsy after PET/CT. AR protein was analyzed in the tumor samples by western blot. Fold change in AR expression was calculated by densitometry analysis. Correlation between imaging and AR protein samples was determined. Results In six of the 12 patients, [ 18 F]-FDHT uptake was significantly higher in the tumor than in the normal brain. These patients also had increased AR protein expression within the tumor. Pearson correlation coefficient analysis for the tumor-to-control normal brain uptake ratio in terms of SUVmean versus AR protein expression, was positive and significant (R = 0.84; p = 0.002). Conclusion [ 18 F]-FDHT-PET/CT could identify increased AR expression in high-grade glioma.

scholarly journals 68Ga-DOTATOC PET/CT-Based Radiomic Analysis and PRRT Outcome: A Preliminary Evaluation Based on an Exploratory Radiomic Analysis on Two Patients

2021 ◽  
Vol 7 ◽  
Author(s):  
Virginia Liberini ◽  
Osvaldo Rampado ◽  
Elena Gallio ◽  
Bruno De Santi ◽  
Francesco Ceci ◽  
...  
Keyword(s):  
Pearson Correlation ◽  
Somatostatin Receptor ◽  
Principal Component ◽  
Receptor Expression ◽  
Whole Body ◽  
Poor Correlation ◽  
Preliminary Evaluation ◽  
Whitney Test ◽  
Mann Whitney Test ◽  
Pet Ct

Aim: This work aims to evaluate whether the radiomic features extracted by 68Ga-DOTATOC-PET/CT of two patients are associated with the response to peptide receptor radionuclide therapy (PRRT) in patients affected by neuroendocrine tumor (NET).Methods: This is a pilot report in two NET patients who experienced a discordant response to PRRT (responder vs. non-responder) according to RECIST1.1. The patients presented with liver metastasis from the rectum and pancreas G3-NET, respectively. Whole-body total-lesion somatostatin receptor-expression (TLSREwb-50) and somatostatin receptor-expressing tumor volume (SRETV wb-50) were obtained in pre- and post-PRRT PET/CT. Radiomic analysis was performed, extracting 38 radiomic features (RFs) from the patients' lesions. The Mann–Whitney test was used to compare RFs in the responder patient vs. the non-responder patient. Pearson correlation and principal component analysis (PCA) were used to evaluate the correlation and independence of the different RFs.Results: TLSREwb-50 and SRETVwb-50 modifications correlate with RECIST1.1 response. A total of 28 RFs extracted on pre-therapy PET/CT showed significant differences between the two patients in the Mann–Whitney test (p < 0.05). A total of seven second-order features, with poor correlation with SUVmax and PET volume, were identified by the Pearson correlation matrix. Finally, the first two PCA principal components explain 83.8% of total variance.Conclusion: TLSREwb-50 and SRETVwb-50 are parameters that might be used to predict and to assess the PET response to PRRT. RFs might have a role in defining inter-patient heterogeneity and in the prediction of therapy response. It is important to implement future studies with larger and more homogeneous patient populations to confirm the efficacy of these biomarkers.

Abstract 328: Capillary Formation and Autologous Regulation of Androgen Receptor Expression in Endothelial Progenitor Cells by DHT: Potential Implications for EPC-Mediated Cardiovascular Repair in Men

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Yuliya Plutino ◽  
Federica Barchiesi ◽  
Nikiana Simigdala ◽  
Bruno Imthurn ◽  
Raghvendra Dubey
Keyword(s):  
Androgen Receptor ◽  
Protein Expression ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Tissue Repair ◽  
Protein Stabilization ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Endothelial Progenitor ◽  
Capillary Formation

Therapeutic use of Endothelial Progenitor Cells (EPCs) is known to repair and protect against cardiovascular damage. Since androgens are associated with cardiovascular protection in men, we investigated the mechanism(s) by which androgens (dihydrotestosterone; DHT) can modulate androgen receptor (AR) dependent EPC activity. Tube/capillary formation and androgen receptor expression by cultured EPCs was assessed using 2D-cultures/co-cultures, western blotting and RT-PCR. Treatment with DHT (100nM) induced capillary/tube formation by EPCs (≈179±3%; p<.05 vs control) and these effects were attenuated by AR antagonist flutamide and AR siRNA. DHT (10-100nM) up-regulated AR protein expression and this effect was abrogated by AR antagonist flutamide (1μM), AR silencing siRNA and cycloheximide (protein synthesis inhibitor). Compared to AR protein, DHT did not induce AR mRNA expression and DHT-induced AR expression was not blocked by the transcription inhibitor actinomycin-D (10ng/ml). Treatment with proteasome inhibitor MG132 (100nM) mimicked the effects of DHT on AR protein expression, moreover, when combined with DHT, the stimulatory effects on AR expression were additive. To ascertain the role of protein stabilization in mediating AR up-regulation in EPCs, the effects of MG132 and DHT on Raf-1, which is known to undergo proteasomal degradation, were assessed. Treatment with MG132, but not DHT, increased Raf-1 expression in EPCs. Moreover, the stimulatory effects of DHT on capillary formation were enhanced in presence of MG132. These findings suggest that DHT up-regulates AR expression and function in EPCs via protein stabilization, however, participation of other pathways cannot be ruled out. In EPCs, DHT induces capillary formation via AR and regulates AR expression in an autologous fashion. Since, androgens induce endothelial growth, and most patients receiving EPCs for cardiovascular repair are older, the low endogenous levels of androgens would decrease the potential of stem cell mediated tissue repair. More importantly, pretreatment of patients or priming of EPCs with androgens/DHT, as well as co-administration of DHT with EPCs may potentiate ARs and EPC mediate cardiovascular tissue repair in men.

scholarly journals The Role of Androgen Receptor Expression in the Curative Treatment of Prostate Cancer with Radiotherapy: A Pilot Study

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Filip Poelaert ◽  
Charles Van Praet ◽  
Anne-Sophie Beerens ◽  
Gert De Meerleer ◽  
Valérie Fonteyne ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Steroid Receptors ◽  
Clinical Information ◽  
Progression Free Survival ◽  
Receptor Expression ◽  
Clinical Relapse ◽  
Gleason Pattern

The androgen receptor (AR) and its signaling pathway play an important role in the development and progression of prostate cancer (PCa). In the setting of primary treatment of PCa with radiotherapy (RT), where the AR can be expected to be of more importance, studies evaluating the AR expression are lacking. The goal of this research is to evaluate AR protein expression in hormone-naive PCa patients treated by RT and investigate its possible prognostic role. Primary biopsy samples of 18 patients treated with primary RT were analyzed including the corresponding clinical information. AR protein expression of the tumor epithelium (with highest Gleason pattern) and the surrounding stroma was quantified using the Quick score for steroid receptors. The differential expression between epithelium and stroma, respectively, between tumor and normal tissue (ΔTumor − ΔBenign >2 versus ≤2), was predictive for clinical progression-free survival in the biopsy samples (P= 0.014). Preliminary results of this research show already a promising role of differential AR expression in predicting clinical relapse after PCa treatment with primary EBRT. Further research is needed to validate these findings. Hopefully this can lead to a better understanding of PCa evolution and eventually lead to better therapy strategies.

scholarly journals Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naïve prostate cancer and are elevated in castration-resistant disease

2013 ◽  
Vol 20 (3) ◽  
pp. 403-413 ◽  
Author(s):  
Tobias Zellweger ◽  
Susanne Stürm ◽  
Silvia Rey ◽  
Inti Zlobec ◽  
Joel R Gsponer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Hormone Receptors ◽  
Expression Profiles ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Poor Overall Survival ◽  
Castration Resistant

Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR210), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR210 was predominantly found in CR PC patients (P<0.0001), pAR210 positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR210, the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR210 and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

scholarly journals Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses’ Health Studies

2018 ◽  
Vol 111 (7) ◽  
pp. 700-708 ◽  
Author(s):  
Kevin H Kensler ◽  
Elizabeth M Poole ◽  
Yujing J Heng ◽  
Laura C Collins ◽  
Benjamin Glass ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Cancer Mortality ◽  
Breast Cancer Mortality ◽  
Receptor Expression ◽  
Health Study ◽  
Breast Cancers ◽  
Linear Association ◽  
Log Linear

Abstract Background Hormone receptor signaling is critical in the progression of breast cancers, although the role of the androgen receptor (AR) remains unclear, particularly for estrogen receptor (ER)–negative tumors. This study assessed AR protein expression as a prognostic marker for breast cancer mortality. Methods This study included 4147 pre- and postmenopausal women with invasive breast cancer from the Nurses’ Health Study (diagnosed 1976–2008) and Nurses’ Health Study II (1989–2008) cohorts. AR protein expression was evaluated by immunohistochemistry and scored through pathologist review and as a digitally quantified continuous measure. Hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer mortality were estimated from Cox proportional hazards models, adjusting for patient, tumor, and treatment covariates. Results Over a median 16.5 years of follow-up, there were 806 deaths due to breast cancer. In the 7 years following diagnosis, AR expression was associated with a 27% reduction in breast cancer mortality overall (multivariable HR = 0.73, 95% CI = 0.58 to 0.91) a 47% reduction for ER+ cancers (HR = 0.53, 95% CI = 0.41 to 0.69), and a 62% increase for ER− cancers (HR = 1.62, 95% CI = 1.18 to 2.22) (P heterogeneity < .001). A log-linear association was observed between AR expression and breast cancer mortality among ER− cancers (HR = 1.14, 95% CI = 1.02 to 1.26 per each 10% increase in AR), although no log-linear association was observed among ER+ cancers. Conclusions AR expression was associated with improved prognosis in ER+ tumors and worse prognosis in ER− tumors in the first 5–10 years postdiagnosis. These findings support the continued evaluation of AR-targeted therapies for AR+/ER− breast cancers.

Regulation of androgen receptor expression at the onset of functional overload in rat plantaris muscle

2003 ◽  
Vol 285 (5) ◽  
pp. R1076-R1085 ◽  
Author(s):  
Won Jun Lee ◽  
Raymond W. Thompson ◽  
Joseph M. McClung ◽  
James A. Carson
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Promoter Activity ◽  
Protein Concentration ◽  
Receptor Expression ◽  
Fibroblast Cells ◽  
Sprague Dawley ◽  
Plantaris Muscle ◽  
Actin Promoter

Skeletal muscle androgen receptor (AR) expression at the onset of functional overload (OV) has not been well described. It is also not known if overload and/or anabolic steroid differentially regulate AR expression. The purpose of this study was to examine AR gene expression at the onset of functional OV in rat plantaris muscle with and without nandrolone decanoate (ND) administration. The functional significance of AR protein induction was examined using skeletal α-actin promoter activity in transiently transfected CV-1 fibroblast cells. Male Sprague-Dawley rats (∼125 g) were functionally overloaded for 1, 3, 7, or 21 days. A subset of animals was given an ND (6 mg/kg) injection at day 0 and then overloaded for 3 days. Control animals underwent sham surgeries. AR protein concentration increased 106 and 279% after 7 and 21 days of OV, respectively. AR mRNA increased 430% after 7 days of OV. AR protein expression in C2C12 murine myotubes subjected to 1% chronic radial stretch for 18 h was elevated 101% compared with control. ND treatment increased AR protein concentration 1,300% compared with controls, and there was no additional effect when ND and OV were combined. ND with 3 days of OV treatment increased AR mRNA expression 50% compared with control. AR overexpression in transiently transfected CV-1 fibroblast cells increased -424 bp skeletal α-actin promoter activity 80 to 1,800% in a dose-dependent fashion. Co-overexpression of either serum response factor (SRF) or active RhoA with AR overexpression induced a synergistic 36- and 28-fold induction of skeletal α-actin promoter. Cotransfection of AR, SRF, and active RhoA induced 180-fold increase in skeletal α-actin promoter activity. In conclusion, AR protein expression is increased after 7 days of functional OV, and this induction is regulated pretranslationally. AR induction in conjunction with SRF and RhoA signaling may be an important regulator of gene expression during overload-induced muscle growth.

scholarly journals Immunohistochemistry for (Pro)renin Receptor in Humans

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Satoshi Morimoto ◽  
Noriko Morishima ◽  
Daisuke Watanabe ◽  
Yoichiro Kato ◽  
Noriyuki Shibata ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Protein Expression ◽  
Expression Pattern ◽  
Receptor Expression ◽  
Whole Body ◽  
Receptor Protein ◽  
Pituitary Hormone ◽  
Human Organ ◽  
Human Organs ◽  
Almost All

The (pro)renin receptor is a multifunctional protein with roles in angiotensin-II-dependent and -independent intracellular cell signaling and roles as an intracellular accessory protein for the vacuolar H+-ATPase, including hormone secretion. While (pro)renin receptor mRNA is widely expressed in various human tissues, localization of (pro)renin receptor protein expression has not yet been systemically determined. Therefore, this study localized (pro)renin receptor protein expression in human organs. Systemic immunohistochemical examination of (pro)renin receptor expression was performed in whole body organs of autopsy cases. (Pro)renin receptor immunostaining was observed in the cytoplasm of cells in almost all human organs. It was observed in thyroid follicular epithelial cells, hepatic cells, pancreatic duct epithelial cells, zona glomerulosa and zona reticularis of the cortex and medulla of the adrenal gland, proximal and distal tubules and collecting ducts of the kidney, cardiomyocytes, and skeletal muscle cells. In the brain, (pro)renin receptor staining was detected in neurons throughout all areas, especially in the medulla oblongata, paraventricular nucleus and supraoptic nucleus of the hypothalamus, cerebrum, granular layer of the hippocampus, Purkinje cell layer of the cerebellum, and the pituitary anterior and posterior lobes. In the anterior lobe of the pituitary gland, all types of anterior pituitary hormone-positive cells showed double staining with (pro)renin receptor. These data showed that (pro)renin receptor protein was expressed in almost all organs of the human body. Its expression pattern was not uniform, and cell-specific expression pattern was observed, supporting the notion that (pro)renin receptor plays numerous physiological roles in each human organ.

scholarly journals ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors

2016 ◽  
Vol 48 (9) ◽  
pp. 688-698 ◽  
Author(s):  
Daniel L. Hertz ◽  
N. Lynn Henry ◽  
Kelley M. Kidwell ◽  
Dafydd Thomas ◽  
Audrey Goddard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Treatment Effectiveness ◽  
Pearson Correlation ◽  
Receptor Expression ◽  
Gene Transcript ◽  
Transcript Expression ◽  
Nucleotide Polymorphisms ◽  
Breast Cancers ◽  
Gene And Protein Expression

Hormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analyzed for ESR1 and PGR gene transcript expression by the reverse transcription polymerase chain reaction based Oncotype DX assay and for ERα and PgR protein expression by immunohistochemistry (IHC) and an automated quantitative immunofluorescence assay (AQUA). Germline genotypes for SNPs in ESR1 ( n = 41) and PGR ( n = 8) were determined by allele-specific TaqMan assays. One SNP in ESR1 (rs9322336) was significantly associated with ESR1 gene transcript expression ( P = 0.006) but not ERα protein expression ( P > 0.05). A PGR SNP (rs518162) was associated with decreased PGR gene transcript expression ( P = 0.003) and PgR protein expression measured by IHC ( P = 0.016), but not AQUA ( P = 0.054). There were modest, but statistically significant correlations between gene and protein expression for ESR1/ERα and PGR/PgR and for protein expression measured by IHC and AQUA (Pearson correlation = 0.32–0.64, all P < 0.001). Inherited ESR1 and PGR genotypes may affect tumor ESR1/ERα and PGR/PgR expression, respectively, which are moderately correlated. This work supports further research into germline predictors of tumor characteristics and treatment effectiveness, which may someday inform selection of hormonal treatments for patients with HR+ breast cancer.

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