Prostate Cancer
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Prostate cancer accounts for over a quarter of all cancers in men. The prostate is a small male sex gland located below the bladder, it produces fluid that becomes semen. Prostate cancer occurs mostly in older men, it is rare before the age of 50, and the risk increases with age. There has been an increase in the incidence of prostate cancer since the early 1980's, most likely due to an increased use of screening using the prostate-specific antigen (PSA) test. However, the role as screening for prostate cancer remains controversial. World-wide about 395,000 men are diagnosed with prostate cancer each year.

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Latest Research Publications
Screening for Prostate Cancer

Information Patients and the Public (31 links)

Information for Health Professionals / Researchers (10 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Theurillat JP, Udeshi ND, Errington WJ, et al.
Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer.
Science. 2014; 346(6205):85-9 [PubMed] Related Publications
Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

Wilmoth MC, Hanlon AL, Ng LS, Bruner DW
Factor analysis of the modified Sexual Adjustment Questionnaire-Male.
J Nurs Meas. 2014; 22(2):241-54 [PubMed] Related Publications
BACKGROUND AND PURPOSE: The Sexual Adjustment Questionnaire (SAQ) is used in National Cancer Institute-sponsored clinical trials as an outcome measure for sexual functioning. The tool was revised to meet the needs for a clinically useful, theory-based outcome measure for use in both research and clinical settings. This report describes the modifications and validity testing of the modified Sexual Adjustment Questionnaire-Male (mSAQ-Male).
METHODS: This secondary analysis of data from a large Radiation Therapy Oncology Group trial employed principal axis factor analytic techniques in estimating validity of the revised tool. The sample size was 686; most subjects were White, older than the age 60 years, and with a high school education and a Karnofsky performance scale (KPS) score of greater than 90.
RESULTS: A 16-item, 3-factor solution resulted from the factor analysis. The mSAQ-Male was also found to be sensitive to changes in physical sexual functioning as measured by the KPS.
CONCLUSION: The mSAQ-Male is a valid self-report measure of sexuality that can be used clinically to detect changes in male sexual functioning.

Hooper G, Gerber E
Measuring the quality of life in men with prostate cancer.
Urol Nurs. 2014 Jul-Aug; 34(4):177-84 [PubMed] Related Publications
Men diagnosed with prostate cancer (PCa) choose treatments based on known side effects that impact health-related quality of life (HRQL). This study evaluated the psychometric properties of the UCLA Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12v2).

Gandini S, Gnagnarella P, Serrano D, et al.
Vitamin D receptor polymorphisms and cancer.
Adv Exp Med Biol. 2014; 810:69-105 [PubMed] Related Publications
It was suggested that vitamin D levels influence cancer development. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D. In fact It has been hypothesized that polymorphisms in the VDR gene affect cancer risk and the relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies. However, results from previous studies on the association of VDR polymorphisms with different cancer types are somewhat contradictory, and the role of VDR in the etiology of cancer is still equivocal. We have performed a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies, including cancer of the skin (melanoma and nonmelanoma skin cancer), ovarian cancer, renal cell carcinoma, bladder cancer, non-Hodgkin lymphoma, leukemia, thyroid carcinoma, esophageal adenocarcinoma, hepatocellular carcinoma, sarcoma, head and neck and oral squamous cell carcinoma. Up to June 2012, we identified 79 independent studies for a total of 52427 cases and 62225 controls. Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1), breast (Fok1, Bsm1, Apa1), colon-rectum (Fok1, Bsm1, Taq1) and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites. Conflicting data have been reported for most malignancies and at present it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that interactions with other factors such as calcium and vitamin D intake, 25(OH)D plasma levels and UV radiation exposure play a decisive role in cancer risk. To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with prediagnostic indicator of vitamin D status.

Related: Breast Cancer Colorectal (Bowel) Cancer Polymorphisms Skin Cancer

Shui I, Giovannucci E
Vitamin D status and cancer incidence and mortality.
Adv Exp Med Biol. 2014; 810:33-51 [PubMed] Related Publications
The role of vitamin D in cancer incidence and mortality has been investigated using several approaches, including using sun exposure as a proxy for vitamin D status, assessing vitamin D intake from food and supplements, using a predicted score to estimate vitamin D status, and directly measuring circulating 25(OH)D. A variety of complementary study designs have been implemented with various strengths and limitations. Although definitive randomized control trial data are lacking, there is strong evidence for a protective relationship of vitamin D and colorectal cancer incidence. Evidence for other cancers is not as consistent. More recently, large pooling projects have begun to investigate rarer cancers, studies have investigated common variation and expression of vitamin D-related genes and their relationships to cancer, and evidence has emerged on the role of vitamin D in cancer survival. Further study is needed to answer important questions that remain about the most affected cancer sites, the timing of vitamin D exposure in relation cancer etiology duringthe life span (e.g., adolescence or adulthood), the dose-response/optimal levels required for the most benefit, and which stages of carcinogenesis (e.g., incidence or progression) are most relevant.

Related: Breast Cancer Colorectal (Bowel) Cancer

Wong J, Xu B, Yeung HN, et al.
Age disparity in palliative radiation therapy among patients with advanced cancer.
Int J Radiat Oncol Biol Phys. 2014; 90(1):224-30 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE/OBJECTIVE: Palliative radiation therapy represents an important treatment option among patients with advanced cancer, although research shows decreased use among older patients. This study evaluated age-related patterns of palliative radiation use among an elderly Medicare population.
METHODS AND MATERIALS: We identified 63,221 patients with metastatic lung, breast, prostate, or colorectal cancer diagnosed between 2000 and 2007 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Receipt of palliative radiation therapy was extracted from Medicare claims. Multivariate Poisson regression analysis determined residual age-related disparity in the receipt of palliative radiation therapy after controlling for confounding covariates including age-related differences in patient and demographic covariates, length of life, and patient preferences for aggressive cancer therapy.
RESULTS: The use of radiation decreased steadily with increasing patient age. Forty-two percent of patients aged 66 to 69 received palliative radiation therapy. Rates of palliative radiation decreased to 38%, 32%, 24%, and 14% among patients aged 70 to 74, 75 to 79, 80 to 84, and over 85, respectively. Multivariate analysis found that confounding covariates attenuated these findings, although the decreased relative rate of palliative radiation therapy among the elderly remained clinically and statistically significant. On multivariate analysis, compared to patients 66 to 69 years old, those aged 70 to 74, 75 to 79, 80 to 84, and over 85 had a 7%, 15%, 25%, and 44% decreased rate of receiving palliative radiation, respectively (all P<.0001).
CONCLUSIONS: Age disparity with palliative radiation therapy exists among older cancer patients. Further research should strive to identify barriers to palliative radiation among the elderly, and extra effort should be made to give older patients the opportunity to receive this quality of life-enhancing treatment at the end of life.

Related: Breast Cancer Colorectal (Bowel) Cancer Lung Cancer USA

Williams RM, Hajiran CJ, Nayeem S, Sooter LJ
Identification of an antibody fragment specific for androgen-dependent prostate cancer cells.
BMC Biotechnol. 2014; 14:81 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Prostate cancer is the most-diagnosed non-skin cancer among males in the US, and the second leading cause of cancer-related death. Current methods of treatment and diagnosis are not specific for the disease. This work identified an antibody fragment that binds selectively to a molecule on the surface of androgen-dependent prostate cancer cells but not benign prostatic cells.
RESULTS: Antibody fragment identification was achieved using a library screening and enrichment strategy. A library of 109 yeast-displayed human non-immune antibody fragments was enriched for those that bind to androgen-dependent prostate cancer cells, but not to benign prostatic cells or purified prostate-specific membrane antigen (PSMA). Seven rounds of panning and fluorescence-activated cell sorting (FACS) screening yielded one antibody fragment identified from the enriched library. This molecule, termed HiR7.8, has a low-nanomolar equilibrium dissociation constant (Kd) and high specificity for androgen-dependent prostate cancer cells.
CONCLUSIONS: Antibody fragment screening from a yeast-displayed library has yielded one molecule with high affinity and specificity. With further pre-clinical development, it is hoped that the antibody fragment identified using this screening strategy will be useful in the specific detection of prostate cancer and in targeted delivery of therapeutic agents for increased efficacy and reduced side effects.

Antonarakis ES, Lu C, Wang H, et al.
AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.
N Engl J Med. 2014; 371(11):1028-38 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
BACKGROUND: The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
METHODS: We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
RESULTS: A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
CONCLUSIONS: Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).

Nguyen PL, Aizer A, Assimos DG, et al.
ACR Appropriateness Criteria® Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer.
Am J Clin Oncol. 2014; 37(3):278-88 [PubMed] Related Publications
PURPOSE: To present the most updated American College of Radiology consensus guidelines formed from an expert panel on the appropriate use of external-beam radiation to manage stage T1 and T2 prostate cancer.
METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
RESULTS: The panel summarized the most recent and relevant literature on the topic and voted on 3 clinical variants illustrating the appropriate dose, techniques, and use of adjuvant hormone therapy with external-beam radiation for low-risk, intermediate-risk, and high-risk prostate cancer. Numerical rating and commentary reflecting the panel consensus was given for each treatment approach in each variant.
CONCLUSIONS: External-beam radiation is a key component of the curative management of T1 and T2 prostate cancer. By combining the most recent medical literature and expert opinion, this guideline can aid clinicians in the appropriate use of external-beam radiation for prostate cancer.

Related: Brachytherapy

Faris SF, Milam DF, Dmochowski RR, Kaufman MR
Urinary diversions after radiation for prostate cancer: indications and treatment.
Urology. 2014; 84(3):702-6 [PubMed] Related Publications
OBJECTIVE: To characterize the presentation and symptom progression culminating in urinary diversion after radiotherapy for prostate cancer at a tertiary care reconstructive urology practice.
MATERIALS AND METHODS: Retrospective review of electronic medical records was performed for all patients between 2005 and 2011 who underwent urinary diversion for urologic complications of radiation therapy for treatment of prostate cancer. We analyzed demographics, type of radiation, presenting symptoms, diagnostic evaluation, and surgical interventions.
RESULTS: Of the 30 patients identified, 20% underwent external beam radiotherapy, 37% underwent brachytherapy, and 43% underwent combination therapy. Average time from radiation treatment until presentation to our institution was 4.6 years. Overall indications for urinary diversion included fistula (37%), end-stage bladder (20%), devastated outlet (27%), and a combination of end-stage bladder and devastated outlet (17%). Types of urinary diversion included cystectomy with conduit diversion, conduit diversion alone, and chronic indwelling suprapubic catheter. Eight patients additionally required bowel diversion for intractable gastrointestinal symptoms. Patients underwent an average of 4.4 procedures attempting to salvage native voiding function before urinary diversion.
CONCLUSION: The reported need for urinary diversion after radiation therapy for prostate cancer is rare and thus indications have not been well characterized. We found that all of our patients with rectourethral fistula had prior placement of brachytherapy seeds. External beam radiotherapy resulted in a higher incidence of end-stage bladder dysfunction, whereas brachytherapy seed placement was more commonly associated with a devastated outlet. Surgical management for end-stage disease included cystectomy with conduit diversion, conduit diversion alone, and indwelling suprapubic catheter.

Related: Brachytherapy

Delouya G, Krishnan V, Bahary JP, et al.
Analysis of the Cancer of the Prostate Risk Assessment to predict for biochemical failure after external beam radiotherapy or prostate seed brachytherapy.
Urology. 2014; 84(3):629-33 [PubMed] Related Publications
OBJECTIVE: To analyze the value of the Cancer of the Prostate Risk Assessment (CAPRA) score to predict biochemical failure (bF) in patients with D'Amico low- or intermediate-risk prostate cancer treated with different radiation techniques.
METHODS: We analyzed 744 patients treated with either external beam radiotherapy (52.7%) or permanent-seed prostate brachytherapy (47.3%) without any androgen deprivation. External beam radiotherapy dose levels were extreme hypofractionation (45 Gy in 9 fractions) in 10%, 76-79.2 Gy (in 1.8-2.0 Gy per fraction) in 32.7%, and 70.2-74 Gy in 10%. All patients had a minimum of 36-month follow-up. Cox regression analysis was used for univariate and multivariate analysis to predict for bF, as per the Phoenix definition (prostate-specific antigen-nadir + 2 ng/mL).
RESULTS: Median follow-up for patients without bF was 56 months (range, 36-114 months). In univariate analysis, CAPRA score as a continuous variable was predictive of bF (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.23-1.79; P <.001), and in multivariate analysis adjusted for treatment type, the HR was 1.39 (95% CI, 1.14-1.71; P = .002). D'Amico intermediate-risk vs low-risk patients had an HR for bF of 1.93 (95% CI, 1.07-3.47; P = .029) in univariate analysis, but the difference was not statistically significant anymore after adjustment for treatment type, (P = .206). The area under the curve of the CAPRA score as a continuous variable at 3 and 5 years was 0.66 and 0.62, respectively (P = .005 for both years).
CONCLUSION: The CAPRA score is predictive of bF. Each 1-point rise increased the risk of bF by 39%, which is comparable to surgical series.

Related: Brachytherapy

Musser JE, Assel M, Mashni JW, et al.
Adult prostate sarcoma: the Memorial Sloan Kettering experience.
Urology. 2014; 84(3):624-8 [PubMed] Related Publications
OBJECTIVE: To present our institutional experience with adult prostate sarcoma over 30 years.
MATERIALS AND METHODS: We reviewed 38 cases of adult prostate sarcoma diagnosed and treated at our institution between 1982 and 2012. Univariate Cox proportional hazards regression was used to determine if there was an association between specific disease characteristics (tumor size, histology, American Joint Committee on Cancer stage, and metastasis at diagnosis) and cancer-specific survival (CSS).
RESULTS: A total of 38 patients were included, with a median age of 50 years (range, 17-73 years). Most men presented with lower urinary tract symptoms (45%), hematuria (24%), or acute urinary retention (21%). Diagnosis was established with prostate needle biopsy (68%) or transurethral resection of the prostate (18%). The predominant histologic subtypes were leiomyosarcoma (13 cases, 34%) and rhabdomyosarcoma (12 cases, 32%). Rhabdomyosarcoma was associated with poorer CSS (hazard ratio, 3.00; 95% confidence interval [CI], 1.13-7.92; P = .027) compared with leiomyosarcoma. We did not observe a significant relationship between tumor size and CSS. Overall, median CSS was 2.9 years (95% CI, 1.5-5.4), with 7.7 years for clinically localized disease (95% CI 2.5; upper bound not reached) and 1.5 years for metastatic disease (95% CI 1.1, 2.7).
CONCLUSION: Adult prostate sarcoma has a poor prognosis, especially in cases of metastatic disease at the time of diagnosis. Surgery remains the standard of care, but it provides limited benefit to those with metastatic disease or as a consolidation therapy after partial response to systemic therapy.

Related: Soft Tissue Sarcomas

Park SY, Kim CK, Park BK, Kwon GY
Comparison of apparent diffusion coefficient calculation between two-point and multipoint B value analyses in prostate cancer and benign prostate tissue at 3 T: preliminary experience.
AJR Am J Roentgenol. 2014; 203(3):W287-94 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to prospectively evaluate the reliability and variability of apparent diffusion coefficient (ADC) calculations between two-point and multipoint b value analyses in prostate cancer and benign prostate tissue.
SUBJECTS AND METHODS: Forty-eight consecutive patients with suspected prostate cancer underwent diffusion-weighted MRI (DWI) at 3 T followed by surgery. DWI was examined under different b values. ADC maps were generated by two different methods: two-point b values (0 and 1000 s/mm(2)) and multipoint b values (0, 100, 300, 700, and 1000 s/mm(2)). Two independent readers measured ADC in the cancers, benign peripheral zone and transition zone, and obturator internus muscle. Statistical analyses were performed using the intraclass correlation coefficient (ICC), correlation of variation (CV), Bland-Altman test, and paired Student t test.
RESULTS: The intermethod ADC calculation revealed excellent reliability for all tissues in both readers: cancer (ICC = 0.979-0.981), transition zone (0.989-0.993), peripheral zone (0.990-0.994), and obturator internus muscle (0.967-0.975). In both readers, the variability of the intermethod ADC calculation was 2.90-3.09% CV in cancer, 1.16-1.48% CV in the transition zone, 1.03-1.29% CV in the peripheral zone, and 2.44-2.62% CV in the obturator internus muscle. For interreader variability, the CVs of ADC calculation for two-point versus multipoint b value analyses in all tissues were 7.21-9.65% versus 7.18-9.01%.
CONCLUSION: For estimating ADC values on 3-T DWI of the prostate, two-point b value analysis seems to present excellent correlation with multipoint b value analysis, with little error in accuracy.

Lawrence EM, Gallagher FA, Barrett T, et al.
Preoperative 3-T diffusion-weighted MRI for the qualitative and quantitative assessment of extracapsular extension in patients with intermediate- or high-risk prostate cancer.
AJR Am J Roentgenol. 2014; 203(3):W280-6 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to prospectively evaluate the value of diffusion-weighted MRI (DWI) for the assessment of extracapsular extension (ECE) in patients with prostate cancer.
SUBJECTS AND METHODS: Between November 2010 and April 2012, 40 patients with intermediate- to high-risk prostate cancer were prospectively recruited. MR images were obtained at 3 T with a phased-array coil. Two independent readers scored the T2-weighted images alone and then in combination with DW images. ROIs were drawn on the apparent diffusion coefficient (ADC) maps, and histogram-derived values were calculated. Whole-mount histopathologic examination was the standard of reference. Reader performance was analyzed, and differences in patient characteristics and histogram-based ADC values, according to ECE status, were evaluated.
RESULTS: ECE was present in 23 of 40 (58%) patients and 23 of 43 (53%) tumors. The sensitivity for side-specific ECE detection significantly increased, from 0.22 to 0.44 for reader 1 and 0.33 to 0.82 for reader 2 (both p < 0.05) without a significant change in specificity for either reader with the addition of DWI and ADC mapping. The positive and negative predictive values for both readers also increased. The ADC parameters of median and 10th and 25th centiles showed a statistically significant difference between tumors with and those without ECE (p < 0.05).
CONCLUSION: The addition of DWI and ADC mapping to T2-weighted MRI improved the accuracy of preoperative detection of ECE. Median and 10th and 25th centile ADC values were significantly associated with the presence of ECE and may be useful in the pretreatment assessment of patients with prostate cancer.

Bastos DA, Dzik C, Rathkopf D, Scher HI
Expanding androgen- and androgen receptor signaling-directed therapies for castration-resistant prostate cancer.
Oncology (Williston Park). 2014; 28(8):693-9 [PubMed] Related Publications
The treatment landscape of castration-resistant prostate cancer (CRPC) has been dramatically changed over the past years with the approval of several new drugs for clinical use. These include androgen axis-targeted therapy and novel drugs with different mechanisms of action, including immunotherapy (sipuleucel-T), radiopharmaceuticals (radium-223), and chemotherapy (cabazitaxel). Based on the growing knowledge that the main driver for patients progressing on standard androgen deprivation therapy is persistent activation of the androgen receptor (AR) signaling axis, new drugs were developed and demonstrated significant efficacy in recent clinical trials, leading to the approval of abiraterone and enzalutamide in several countries. In this article, we review the most recent advances in AR-directed therapies for CRPC, promising new agents under development, cross-resistance, and mechanisms of resistance for the new-generation AR-targeted agents.

Related: Signal Transduction AR: androgen receptor

Farrow JM, Yang JC, Evans CP
Autophagy as a modulator and target in prostate cancer.
Nat Rev Urol. 2014; 11(9):508-16 [PubMed] Related Publications
Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.

Li N, Chen M, Truong S, et al.
Determinants of Gli2 co-activation of wildtype and naturally truncated androgen receptors.
Prostate. 2014; 74(14):1400-10 [PubMed] Related Publications
BACKGROUND: Gli2, a transcription factor in the Hedgehog pathway, is overexpressed in castrate-resistant prostate cancer (PCa). Previously we showed that Gli2 overexpression increased transcriptional activity of androgen receptor (AR) and conferred androgen growth-independence to normally growth-dependent PCa cells. Here we localized the regions of AR-Gli2 protein interaction and determined the domains within Gli2 needed for AR co-activation.
METHODS: Co-immunoprecipitation and GST-pulldown assays were used to define AR-Gli binding domains. Co-activation assays using androgen-responsive promoter reporters were used to define Gli2 regions needed for AR co-activation. Chromatin immunoprecipitation (ChIP) assays were used to confirm nuclear interactions of Gli2 with AR in PCa cells.
RESULTS: The Gli2 C-terminal domain (CTD) is sufficient for AR co-activation. Two elements within the CTD were required: (1) an AR binding domain within aa628-897; and (2) at least part of the Gli2 transactivation domain within aa1252-1586. In turn, Gli2 binds the tau5/AF5 ligand-independent activation domain in the AR N-terminus. Mutations in the WxxLF motif in tau5/AF5 greatly diminished binding to Gli2-CTD. Gli2 interaction with AR tau5/AF5 was further substantiated by the ability of Gli2/Gli2-CTD to co-activate truncated AR splice variants (AR-V7/ARV567es). ChIP assays confirmed that Gli2 associates with chromatin at androgen response elements found near androgen-responsive genes in LNCaP cells. These assays also showed that AR associates with chromatin containing a Gli-response element near a Gli-responsive gene.
CONCLUSION: Our findings indicate that Gli2 overexpression in PCa cells might support development of castration resistant PCa through AR co-activation and suggests that AR might modulate transcription from Gli2.

Related: GLI

Liu J, Lau EY, Chen J, et al.
Polysaccharopeptide enhanced the anti-cancer effect of gamma-tocotrienol through activation of AMPK.
BMC Complement Altern Med. 2014; 14:303 [PubMed] Related Publications
BACKGROUND: Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy.
METHOD: We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer.
RESULT: We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo.
CONCLUSION: Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

Evan Pollack C, Wang H, Bekelman JE, et al.
Physician social networks and variation in rates of complications after radical prostatectomy.
Value Health. 2014; 17(5):611-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
OBJECTIVES: Variation in care within and across geographic areas remains poorly understood. The goal of this article was to examine whether physician social networks-as defined by shared patients-are associated with rates of complications after radical prostatectomy.
METHODS: In five cities, we constructed networks of physicians on the basis of their shared patients in 2004-2005 Surveillance, Epidemiology and End Results-Medicare data. From these networks, we identified subgroups of urologists who most frequently shared patients with one another. Among men with localized prostate cancer who underwent radical prostatectomy, we used multilevel analysis with generalized linear mixed-effect models to examine whether physician network structure-along with specific characteristics of the network subgroups-was associated with rates of 30-day and late urinary complications, and long-term incontinence after accounting for patient-level sociodemographic, clinical factors, and urologist patient volume.
RESULTS: Networks included 2677 men in five cities who underwent radical prostatectomy. The unadjusted rate of 30-day surgical complications varied across network subgroups from an 18.8 percentage-point difference in the rate of complications across network subgroups in city 1 to a 26.9 percentage-point difference in city 5. Large differences in unadjusted rates of late urinary complications and long-term incontinence across subgroups were similarly found. Network subgroup characteristics-average urologist centrality and patient racial composition-were significantly associated with rates of surgical complications.
CONCLUSIONS: Analysis of physician networks using Surveillance, Epidemiology and End Results-Medicare data provides insight into observed variation in rates of complications for localized prostate cancer. If validated, such approaches may be used to target future quality improvement interventions.

Related: USA

Reed SD, Stewart SB, Scales CD, Moul JW
A framework to evaluate the cost-effectiveness of the NADiA ProsVue slope to guide adjuvant radiotherapy among men with high-risk characteristics following prostatectomy for prostate cancer.
Value Health. 2014; 17(5):545-54 [PubMed] Related Publications
OBJECTIVES: The NADiA ProsVue is a prognostic system that measures prostate-specific antigen slope to identify men at lower risk of clinical recurrence of prostate cancer after radical prostatectomy. We developed a decision-modeling framework to evaluate its cost-effectiveness to guide the use of adjuvant radiotherapy (ART).
METHODS: We populated the model using patient-level data and external sources. Patients were classified as intermediate risk or high risk on the basis of Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) nomogram and then stratified by the ProsVue slope (≤2 pg/mL/mo; >2 pg/mL/mo) and receipt of ART. In sensitivity analyses, we varied the effect of the ProsVue slope on the use of ART and other model parameters.
RESULTS: The cost-effectiveness of the ProsVue-guided strategy varied widely because of small differences in quality-adjusted life-years (QALYs) at 10 years. In the intermediate-risk group, when the use of ART decreased from 20% (standard care) to 7.5% among patients with a ProsVue slope value of 2 pg/mL/mo or less, the incremental cost-effectiveness ratio was $25,160/QALY. In the high-risk group, the use of ART would have to decrease from 40% (standard care) to 11.5% among those with a ProsVue slope value of 2 pg/mL/mo or less to obtain a ratio of $50,000/QALY. The cost-effectiveness ratios were sensitive to varying benefits of salvage therapy, quality of life, and costs of ART and ProsVue testing.
CONCLUSIONS: The effect of the ProsVue system on costs will be dependent on the extent to which ART decreases among men identified as having a low risk of recurrence. Its effect on QALYs will remain conditional on uncertain clinical and quality-of-life benefits associated with ART.

Globa T, Saptefrţi L, Ceauşu RA, et al.
Mast cell phenotype in benign and malignant tumors of the prostate.
Pol J Pathol. 2014; 65(2):147-53 [PubMed] Related Publications
The molecular phenotypic heterogeneity of mast cells (MCs) makes them attractive as potential therapeutic targets in anti-cancer adjuvant therapy. Mast cell aggregations observed in tumors suggested their involvement in tumor pathogenesis. Despite several studies using mast cell tryptase, MCs' involvement in the progression of prostate tumors has not been demonstrated. The aim of our study was to identify and quantify the phenotypic heterogeneity of MCs in prostate lesions. Our study included 7 cases of normal prostate, 25 cases of benign epithelial hyperplasia and 64 cases of prostate carcinoma. MCs were immunohistochemically assessed using three markers: tryptase, chymase and CD117. Two immunophenotypes of MCs were identified in benign lesions: tryptase+/CD117+/chymase- and tryptase-/chymase+/CD117+, located in peritumoral areas. Intratumoral MC phenotype of malignant lesions was characterized by tryptase+/chymase+/CD117+, while in the peritumoral areas three different MCs phenotypes were identified: tryptase+/chymase+/CD117-, tryptase+/CD117+/chymase- and chymase+/CD117+/tryptase-. Our results suggest the correlation of chymase positive MCs of the peritumoral areas and CD117 positive MCs of the intratumoral areas with tumor grade.

Huang H, Chen W, Liu Q, et al.
Inhibition of N-acetylglucosaminyltransferase V enhances sensitivity of radiotherapy in human prostate cancer.
Biochem Biophys Res Commun. 2014; 451(3):345-51 [PubMed] Related Publications
The purpose of this study was to investigate the relationship between N-acetylglucosaminyltransferase V (GnT-V) and radiation sensitivity of prostate cancer (PCa) cells both in vitro and in vivo. Firstly, the GnT-V expression was studied in 84 cases of PCa tissues, in which higher level of GnT-V was detected more frequently in the advanced tumors. Secondly, the GnT-V stably suppressed cell lines PCa/1079 (Lncap/1079 and PC3/1079) were constructed from PCa cell lines (Lncap and PC3) in vitro. Attenuation of GnT-V inhibited cell proliferation, migration and increased apoptosis, which resulted in enhanced radiation sensitivity of PCa cells. The underlying mechanism may be relevant to the increasing ratio of Bax/Bcl-2, the blocking transcription of NF-κB and the reduction of cell cycle G2-M arrest. Finally, in in vivo study, compared with control groups, the irradiated PCa xenograft nude mice of PCa/1079 indicated to reduce tumor-growth rate and enhance survival time. Summary, our studies showed that inhibition of GnT-V probably improved PCa cells' radiation sensitivity.

Related: Apoptosis

Ness N, Andersen S, Valkov A, et al.
Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer.
Prostate. 2014; 74(14):1452-61 [PubMed] Related Publications
BACKGROUNDS: The adaptive immune system can potentially have dual roles in cancer development and progression by contributing to or suppressing tumor progression and metastasis. The aim of this study was to evaluate the prognostic impact of adaptive immune cells residing in different tumor compartments in prostate cancer.
METHODS: Tissue microarrays from 535 patients were constructed from viable and representative tumor epithelial and stromal areas of primary PC tumors, as well as from normal epithelial and stromal areas. Immunohistochemistry was used to evaluate the density of CD3+, CD4+, CD8+, and CD20+ lymphocytes in both tumor epithelial and tumor stromal areas.
RESULTS: In univariate analysis, a high density of CD3+ (P = 0.037) and CD8+ lymphocytes (P = 0.010) in tumor epithelial areas was associated with significantly shorter biochemical failure-free survival. When analyzing both tumor epithelial and stromal tissue compartments as one entity, similar relationships were observed for CD3+ (P = 0.046), CD4+ (P = 0.026), and CD8+ (P = 0.003) lymphocytes. In multivariate analysis, high densities of CD8+ lymphocytes limited to tumor epithelial areas (HR = 1.45, P = 0.032), as well as in the total tumor tissue (HR = 1.57, P = 0.007), were independent negative prognostic factors for biochemical failure-free survival.
CONCLUSIONS: A high density of CD8+ lymphocytes, especially in tumor epithelial areas, is an independent negative prognostic factor for biochemical failure-free survival.

Leibowitz-Amit R, Alimohamed N, Vera-Badillo FE, et al.
Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.
Prostate. 2014; 74(14):1462-4 [PubMed] Related Publications
BACKGROUND: Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC).
METHODS: We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre.
RESULTS: All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA.
CONCLUSIONS: Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

Maier C, Herkommer K, Luedeke M, et al.
Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations.
Prostate. 2014; 74(14):1444-51 [PubMed] Related Publications
BACKGROUND: One of the known risk factors for prostate cancer (PrCa) is germline mutations in the BRCA2 gene. Previous searches for clinical characteristics which could identify a subgroup of patients enriched for mutation carriers revealed early onset and aggressive PrCa as useful parameters, but they are rather unspecific.
METHODS: Identification of BRCA2 mutation carriers by sequencing all exons of BRCA2 in a German cohort of 382 familial PrCa cases and of 92 sporadic PrCa cases with early onset (≤60 years). To define a subgroup of PrCa patients enriched for BRCA2 mutation carriers, we used clinical parameters including a detailed family history (FH) for PrCa and breast cancer.
RESULTS: Five BRCA2 mutations and ten variants of unknown significance (VUS) were identified. While the VUS were evenly distributed among the groups, mutation carriers were lacking from the sporadic cases and over represented among familial cases with aggressive disease. High prostate specific antigen (PSA) at diagnosis (>20 ng/ml) was the only criterion with significant enrichment of mutation carriers (6.4%, P = 0.0005). In men with aggressive disease, death from PrCa (6.3% including FH of lethal PrCa; P = 0.05) and FH of both prostate and breast cancer (4.8%; P = 0.3) increased the frequency of mutation carriers. Larger studies and/or meta-analyses are needed to validate these parameters.
CONCLUSIONS: We have identified three potentially useful criteria, high PSA, death from PrCa (patient or FH), and aggressive PrCa in combination with FH of breast and prostate cancer. If confirmed, they may become useful for the decision which patients may benefit from BRCA2 testing.

Related: BRCA2 KLK3

Klyushnenkova EN, Riabov VB, Kouiavskaia DV, et al.
Breaking immune tolerance by targeting CD25+ regulatory T cells is essential for the anti-tumor effect of the CTLA-4 blockade in an HLA-DR transgenic mouse model of prostate cancer.
Prostate. 2014; 74(14):1423-32 [PubMed] Related Publications
INTRODUCTION: Recent studies suggest that the cancer immunotherapy based on the blockade of the CTLA-4-mediated inhibitory pathway is efficacious only in select populations, predominantly for immunogenic tumors or when delivered in combination with modalities that can break immunologic tolerance to tumor antigens.
METHODS: We studied the effect of CD25+ cell depletion and CTLA-4 blockade on the growth of Transgenic Mouse Adenocarcinoma of Prostate (TRAMP)-PSA tumor cells in DR2bxPSA F1 mice. In these mice, immunological tolerance to PSA was established in a context of the HLA-DRB1*1501(DR2b) allele.
RESULTS: In our model, single administration of anti-CD25 antibody prior to tumor inoculation significantly increased IFN-γ production in response to the CD8 T cell epitope PSA65-73 , and delayed TRAMP-PSA tumor growth compared to mice treated with isotype control antibodies. In contrast, the anti-tumor effect of the anti-CTLA-4 antibody as a monotherapy was marginal. The combinatory treatment with anti-CD25/anti-CTLA-4 antibodies significantly enhanced anti-tumor immunity and caused more profound delay in tumor growth compared to each treatment alone. The proportion of tumor-free animals was higher in the group that received combination treatment (21%) compared to other groups (2-7%). The enhanced anti-tumor immunity in response to the CD25 depletion or CTLA-4 blockade was only seen in the immunogenic TRAMP-PSA tumor model, whereas the effect was completely absent in mice bearing poorly immunogenic TRAMP-C1 tumors.
DISCUSSION: Our data suggest that breaking immunological tolerance to "self" antigens is essential for the therapeutic effect of CTLA-4 blockade. Such combinatory treatment may be a promising approach for prostate cancer immunotherapy.

Related: Monoclonal Antibodies

Calastretti A, Gatti G, Quaresmini C, Bevilacqua A
Down-modulation of Bcl-2 sensitizes PTEN-mutated prostate cancer cells to starvation and taxanes.
Prostate. 2014; 74(14):1411-22 [PubMed] Related Publications
BACKGROUND: The critical role of PTEN in regulating the PI3K/Akt/mTOR signaling pathway raises the possibility that targeting downstream effectors of the PI3K pathway, such as Bcl-2, might be an effective anti-proliferative strategy for PTEN-deficient prostate cancer cells.
METHODS: Four prostate cancer cell lines (LNCaP, PC3, DU145, 22Rv1) were assayed for their levels of total Akt and Ser473 phosphorylated Akt (p-Akt) by Western Blotting; their growth rates and sensitivity to different doses of paclitaxel were determined by cell counts after Trypan Blue dye exclusion assay. Cells were subjected to different combinations of starvation (growth factors and/or aminoacids withdrawal), paclitaxel treatment and Bcl-2 silencing by siRNA. Cell viability was evaluated by Trypan Blue dye exclusion assay, Propidium Iodide (PI) and Annexin-V/PI staining.
RESULTS: We assessed the sensitivity of different prostate cancer cell lines to starvation and we observed a differential response correlated to the levels of Akt activation. The four prostate cancer cell lines also showed different sensitivity to taxol treatments; LNCaP and 22Rv1 cells were more resistant to paclitaxel than DU145 and PC3 cells. Combining taxol with growth factors and aminoacids deprivation leaded to a more than additive reduction of cell viability compared to single treatments in PTEN-mutant LNCaP cells. Down-modulation of anti-apoptotic Bcl-2 protein by siRNA sensitized LNCaP cells to taxanes and starvation induced cell death.
CONCLUSIONS: Silencing Bcl-2 in PTEN-mutated prostate cancer cells enhances the apoptotic effects of combined starvation and taxol treatments, indicating that inhibition of Bcl-2 may be of significant value in PTEN-mutant tumor therapy.

Related: PTEN Paclitaxel

Norström MM, Rådestad E, Stikvoort A, et al.
Novel method to characterize immune cells from human prostate tissue.
Prostate. 2014; 74(14):1391-9 [PubMed] Related Publications
BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common benign adenoma and prostate cancer is the most frequent malignancy in men over 50 years of age in the Western world, where it remains a significant health problem. Prostate lesions are known to contain immune cells, which may contribute to the immune control of tumor progression. However, due to their low numbers and restricted access to necessary material it is difficult to isolate immune cells from prostate tissue to characterize their immunological features.
METHODS: An efficient and robust method was developed to process prostate tissue and isolate immune cells for phenotypic analysis by multicolor flow cytometry as downstream application. Fresh prostate tissue from 11 patients undergoing surgery for bladder outlet obstruction due to BPH was processed to evaluate the number, viability, yield, and frequency of various immune cell types.
RESULTS: The presented method does not include enzymatic digestion nor incubation steps at 37 °C, increasing cellular viability and avoiding possible phenotypic modification. Various immune cell populations were detected in all patient samples and the median cellular viability was 90%. The number of detected events of individual cell populations varied between patients. The median frequency of different immune cell populations also varied, being 87% for the CD3- and 15% for the CD3+ cell population.
CONCLUSIONS: This novel method will allow the phenotypic characterization of immune cell populations present in tumor tissue of prostate cancer patients and promote development of novel approaches to immunotherapy of the disease.

Lázaro-Ibáñez E, Sanz-Garcia A, Visakorpi T, et al.
Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes.
Prostate. 2014; 74(14):1379-90 [PubMed] Related Publications
BACKGROUND: Extracellular vesicles (EVs) are cell-derived membrane vesicles. EVs contain several RNAs such as mRNA, microRNAs, and ncRNAs, but less is known of their genomic DNA (gDNA) content. It is also unknown whether the DNA cargo is randomly sorted or if it is systematically packed into specific EV subpopulations. The aim of this study was to analyze whether different prostate cancer (PCa) cell-derived EV subpopulations (apoptotic bodies, microvesicles, and exosomes) carry different gDNA fragments.
METHODS: EV subpopulations were isolated from three PCa cell lines (LNCaP, PC-3, and RC92a/hTERT) and the plasma of PCa patients and healthy donors, and characterized by transmission electron microscopy, nanoparticle tracking analysis and total protein content. gDNA fragments of different genes were detected by real time quantitative PCR and confirmed by DNA sequencing.
RESULTS: We report that the concentration of EVs was higher in the cancer patients than in the healthy controls. EV subpopulations differed from each other in terms of total protein and DNA content. Analysis of gDNA fragments of MLH1, PTEN, and TP53 genes from the PCa cell-derived EV subpopulations showed that different EVs carried different gDNA content, which could even harbor specific mutations. Altogether, these results suggest that both nucleic acids and proteins are selectively and cell-dependently packed into the EV subtypes.
CONCLUSIONS: EVs derived from PCa cell lines and human plasma samples contain double-stranded gDNA fragments which could be used to detect specific mutations, making EVs potential biomarkers for cancer diagnostics and prognostics.

Related: Apoptosis PTEN

Johnson AM, Zuhlke KA, Plotts C, et al.
Mutational landscape of candidate genes in familial prostate cancer.
Prostate. 2014; 74(14):1371-8 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Family history is a major risk factor for prostate cancer (PCa), suggesting a genetic component to the disease. However, traditional linkage and association studies have failed to fully elucidate the underlying genetic basis of familial PCa.
METHODS: Here, we use a candidate gene approach to identify potential PCa susceptibility variants in whole exome sequencing data from familial PCa cases. Six hundred ninety-seven candidate genes were identified based on function, location near a known chromosome 17 linkage signal, and/or previous association with prostate or other cancers. Single nucleotide variants (SNVs) in these candidate genes were identified in whole exome sequence data from 33 PCa cases from 11 multiplex PCa families (3 cases/family).
RESULTS: Overall, 4,856 candidate gene SNVs were identified, including 1,052 missense and 10 nonsense variants. Twenty missense variants were shared by all three family members in each family in which they were observed. Additionally, 15 missense variants were shared by two of three family members and predicted to be deleterious by five different algorithms. Four missense variants, BLM Gln123Arg, PARP2 Arg283Gln, LRCC46 Ala295Thr and KIF2B Pro91Leu, and one nonsense variant, CYP3A43 Arg441Ter, showed complete co-segregation with PCa status. Twelve additional variants displayed partial co-segregation with PCa.
CONCLUSIONS: Forty-three nonsense and shared, missense variants were identified in our candidate genes. Further research is needed to determine the contribution of these variants to PCa susceptibility.

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