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PURPOSE - To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity.
METHODS AND MATERIALS - Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy.
RESULTS - Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay.
CONCLUSIONS - BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT.
Copyright © 2019. Published by Elsevier Inc.
Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.
BACKGROUND - Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer.
METHODS - Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed. Immunohistochemistry with double staining for MAGI2 and p63 was performed and analyzed by image analysis as percent of analyzed area (%AREA). Multivariable logistic regression was used to correlate MAGI2 expression with clinical outcomes. Generalized Estimating Equations (GEE) with linear and logistic regression was used to correlate MAGI2 with intrapatient histology.
RESULTS - MAGI2 %AREA was inversely associated with progression from HGPIN to adenocarcinoma of low to high Gleason score (OR, 0.980; slope, -0.02; P = 0.005) and HGPIN to cancer of any Gleason score (OR, 0.969; P = 0.007). After adjusting for grade, stage, and margin status, MAGI2 %AREA was a significant independent predictor of biochemical recurrence (BCR) (OR, 0.936; 95%CI, 0.880-0.996; P = 0.037; bootstrap P = 0.017). The addition of MAGI2 %AREA to these standard clinical parameters improved accuracy of predicting BCR by 2.9% (91.0% vs 88.1%).
CONCLUSIONS - These results reveal that MAGI2 expression is reduced during prostate cancer progression and that retention of MAGI2 signal reduces odds of BCR. The study results further suggest a possible role of MAGI2 in prostate neoplasia. Decreased MAGI2 expression may help predict prostate cancer aggressiveness and provide new insight for treatment decisions and post-operative surveillance intervals.
© 2018 Wiley Periodicals, Inc.
PURPOSE/OBJECTIVES - Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model.
METHODS AND MATERIALS - Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues.
RESULTS - There were significant alterations in the ICP (P<.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho-associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT.
CONCLUSIONS - RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary.
Copyright © 2017 Elsevier Inc. All rights reserved.
EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.
Androgens regulate the proliferation and differentiation of prostatic epithelial cells, including prostate cancer (PCa) cells in a context-dependent manner. Androgens and androgen receptor (AR) do not invariably promote cell proliferation; in the normal adult, endogenous stromal and epithelial AR activation maintains differentiation and inhibits organ growth. In the current study, we report that activation of AR differentially regulates the proliferation of human prostate epithelial progenitor cells, NHPrE1, in vitro and in vivo. Inducing AR signaling in NHPrE1 cells suppressed cell proliferation in vitro, concomitant with a reduction in MYC expression. However, ectopic expression of AR in vivo stimulated cell proliferation and induced development of invasive PCa in tissue recombinants consisting of NHPrE1/AR cells and rat urogenital mesenchymal (UGM) cells, engrafted under renal capsule of adult male athymic mice. Expression of MYC increased in the NHPrE1/AR recombinant tissues, in contrast to the reduction seen in vitro. The inhibitory effect of AR signaling on cell proliferation in vitro were reduced by co-culturing NHPrE1/AR epithelial cells with prostatic stromal cells. In conclusion, these studies revealed that AR signaling differentially regulates proliferation of human prostatic epithelia cells in vitro and in vivo through mechanisms involving stromal/epithelial interactions.
OBJECTIVES - We compared the utility of membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) and α-methylacyl CoA (AMACR) by immunohistochemistry in diagnosing prostatic adenocarcinoma.
METHODS - Seventy-eight radical prostatectomies were used to construct three tissue microarrays with 512 cores, including benign prostatic tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma. AMACR and MAGI-2 immunohistochemistry were evaluated by visual and image analysis.
RESULTS - MAGI-2 and AMACR were significantly higher in adenocarcinoma and HGPIN compared with benign tissue. At H-score cutoffs of 300 and 200, MAGI-2 was more accurate in distinguishing benign from malignant glands than AMACR. Areas under the curve by image and visual analysis were 0.846 and 0.818 for MAGI-2 and 0.937 and 0.924 for AMACR, respectively. The accuracy of MAGI-2 in distinguishing benign from malignant glands on the same core was higher (95% vs 88%).
CONCLUSIONS - MAGI-2 could represent a useful adjunct for diagnosis of prostatic adenocarcinoma, especially when AMACR is not discriminatory.
© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: email@example.com.
BACKGROUND - Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
METHODS - Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
RESULTS - SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
CONCLUSION - Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
PURPOSE - Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC.
PATIENTS AND METHODS - A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS).
RESULTS - Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials.
CONCLUSION - Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
© 2016 by American Society of Clinical Oncology.