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Item does not contain fulltext Identification of new markers for diagnosis and new targets for therapy would represent a considerable advance in the treatment of prostate cancer. Differential display code 3 (DD3(PCA3)) is a novel gene with characteristics that indicate its potentially valuable role in early identification of malignancy and in the construction of interventions directed specifically toward malignantly transformed cells. DD3(PCA3) has a messenger RNA product that is highly overexpressed in tumors. Compared with other genetic markers that are associated with prostate tissue, DD3(PCA3) is the most specific marker for malignant disease. Indeed, it is not expressed in any other normal human tissue, including breast, bladder, testis, gastrointestinal organ, and musculoskeletal tissue. This specific relation of DD3(PCA3) to prostate tissue has been confirmed by reverse transcription-polymerase chain reaction analysis. Clonal investigation of the DD3(PCA3) transcription unit indicates that the gene has 4 distinct exons, which can give rise to a number of differently sized transcripts. Open reading frame analysis has also confirmed that the DD3(PCA3) exons are populated by an unusual number of stop codons. The dramatic prostate-specific expression and pronounced upregulation of DD3(PCA3) in prostate cancer suggest a unique transcriptional regulation. A quantitative assay for DD3(PCA3) would be a potentially valuable tool for the detection of malignant cells in blood, urine, or other clinical specimens, and it could have important implications for the earlier diagnosis and molecular staging of prostate cancer. Although further studies are needed, gene therapies based on identification to delineate the range of transcription factors that interact with the DD3(PCA3) promoter represent a promising area for preclinical investigation.

Contains fulltext : 81968.pdf (Publisher’s version ) (Open Access) Serum PSA has shown to be the most valuable tool in the detection, staging and monitoring of prostate cancer (PCa). However, the substantial overlap in serum PSA values between men with non-malignant prostatic diseases and PCa is the limitation of PSA as a prostate tumor marker. In patients with serum PSA values between 3-10 ng/ml, the negative biopsy rate is 60-75%. In this thesis, the focus is on improving the specificity in PCa diagnosis by using PCa-specific genes in adjunct to serum PSA testing. Prostate cancer gene 3 (PCA3) was identified as the prime candidate biomarker for the detection of PCa. The strong association between PCA3 over-expression and malignant transformation of prostate epithelium has prompted its potential use as a biomarker for the diagnosis of PCa. Since PCA3 is a non-coding RNA, an RNA-based molecular assay for PCA3 was developed. The studies in this thesis demonstrated and validated the potential of an RUO quantitative PCA3-based urine test to detect PCa cells in urinary sediments after digital rectal examination (DRE) and showed that PCA3 could aid in the prediction of biopsy outcome. PCa is a heterogeneous disease and the combination of tests for PCA3 and TMPRSS2-ERG gene-fusions were shown to improve the sensitivity without compromising specificity. In 2006, the RUO-PCA3 test has been translated to an IVD validated technology platform (Gen-Probe Inc.) and the CE-marked version of this test is the first, fully translated RNA-based molecular diagnostic urine test for PCa that is now available to urologists. This test can contribute to the decision making in the diagnosis of PCa. The value of the PCA3 test to predict the biological behaviour of prostate tumors is not fully matured, although some studies show promising results. Non-invasive biomarker-based assays for the diagnosis of PCa have now become reality. RU Radboud Universiteit Nijmegen, 02 juli 2010 Promotores : Schalken, J.A., Witjes, J.A., Mulders, P.F.A. 167 p.

Contains fulltext : 81903schalken.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dutasteride is commonly used in patients that are also at risk for prostate cancer (PCa). Therefore, the influence of dutasteride on PCa markers has to be studied. To date, only the effect of dutasteride on serum prostate-specific antigen (PSA) has been studied. This was the first study to investigate the effect of dutasteride on the new PCa marker PCA3, longitudinally and in a dose dependent manner. METHODS: From April 25, 2005 to October 31, 2006, 16 subjects with benign prostatic hyperplasia (BPH) and 9 subjects with clinically localized PCa were enrolled at the urological outpatient clinics of one university hospital and one community hospital. Eight subjects with BPH and five with PCa received 0.5 mg dutasteride once daily for 3 months, eight with BPH and four with PCa received 3.5 mg. No subjects were withdrawn because of adverse effects. RESULTS: In all four groups both 0.5 and 3.5 mg dutasteride had a variable effect on the PCA3 score. In contrast, its other effects were consistent as it rapidly reduced serum DHT by >or=90%, over time increased serum T by 20-30%, over time halved serum PSA and decreased prostate volume by 10-16%. CONCLUSIONS: In this exploratory/pilot study the effect of dutasteride on the PCA3 score was variable. This should be taken into account while using PCA3 in diagnostics. As this study was exploratory, the influence of androgen-deprivation therapy on the PCA3 score should be analyzed further.

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Item does not contain fulltext We identified DD3(PCA3) as one of the most prostate cancer-specific genes at present (M. J. Bussemakers et al. Cancer Res., 59: 5975-5979, 1999). Consequently, DD3(PCA3) is an interesting candidate for use as a diagnostic and/or prognostic marker. In this study we developed a method for the accurate quantification of DD3(PCA3) mRNA, using real-time quantitative reverse transcription-PCR. DD3(PCA3) was expressed at low levels in normal prostate but not in 21 selected other normal tissues, blood, or 39 tumor samples other than prostate. The diagnostic and prognostic value of DD3(PCA3) in normal, hyperplastic, and malignant prostate tissues was determined and compared with another promising tumor marker for prostate cancer, telomerase reverse transcriptase (hTERT gene), the expression of which is related to telomerase activity. Sensitivity and specificity estimates for both genes were calculated as the area under the receiver-operating characteristics curve (AUC-ROC). DD3(PCA3) (AUC-ROC, 0.98) demonstrated better diagnostic efficacy than hTERT (AUC-ROC, 0.88). Moreover, the median increase in mRNA expression in tumor tissues compared with nonmalignant prostate tissues was much higher for DD3(PCA3) (34-fold) than for hTERT (6-fold). In tumor tissues, the median expression of DD3(PCA3) was much higher than hTERT (5849 versus 10 normalized mRNA copies). A significant relationship was observed only between tumor stage and hTERT gene expression. We conclude that expression of the DD3(PCA3) gene is a very sensitive and specific marker for the detection of prostate tumor cells in a high background of normal (prostate) cells. Consequently, DD3 measurements may be used for clinical application in prostate needle biopsies or bodily fluids such as blood, ejaculate, urine, or prostate massage fluid.