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Query: UMLS:C0600139 (Prostate Cancer)
 4,540 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chemoprevention (CP) strategy has evolved for conducting efficient clinical trials for prostate cancer (PCa) prevention. It integrates five key components, including agents, biomarkers, cohorts, designs, and endpoints. The rationale for the CP strategy relates to the natural history of prostate cancer. There is a wide array of natural and synthetic agents that hold promise for inhibiting, reversing, or modulating the transition from normal to precancer and from precancer to cancer. These agent classes include antiandrogens, antiestrogens, phytoestrogens, antioxidants, anti-inflammatory (proapoptotic) agents, antiproliferation/antidifferentiation agents, signal transduction modulators of receptor tyrosine kinase and ras farnesylation, antiangiogenesis agents, insulinlike growth factor (IGF)-1, peroxisome proliferator-activator receptor modulators (-gamma and -delta), and gene-based interventions. Biomarkers and endpoints are guided by the level of evidence required (eg, phase 1, 2, 3). Two candidate surrogate endpoints (SE) based on histology are high-grade prostatic intraepithelial neoplasia (HGPIN) and computer-assisted image analysis of dysplastic lesions. Phase 1 trials use standard endpoints of safety, pharmacokinetics and limited pharmacodynamics. Phase 2 trials use endpoints of modulation of biomarkers and correlation with histology. Phase 3 trials use endpoints of clinical benefit, such as cancer incidence reduction and quality of life. Validation of a biomarker as a SE involves correlation of the biomarker with clinical benefit. Cohorts (target populations) for phase 2/3 trials include the general population of men over age 50 with a normal prostate-specific antigen (PSA), subjects with a strong family history of PCa, subjects with elevated PSA/negative biopsy, and subjects with HGPIN/negative biopsy. These at-risk populations reflect key individual risk factors (age, race, serum PSA [free/total]; serum IGF-1/IGF binding protein (IGFBP)-3; 1, 25(OH)(2) D3; family history of PCa; carriers of PCa susceptibility genes [ELAC2, CYP3A4, SRD5A2, etc.]; and histology such as atypia and HGPIN) that could be combined into a multivariate risk model for PCa. The probability of cancer risk (recurrence) is a key factor that impacts on the clinical trial design (power, sample size, and primary endpoint). Multivariate predictive mathematical models for biochemical recurrence after radical prostatectomy by decreasing sample size and time to clinical outcomes maximize trial efficiency and identify the patients most likely to benefit from secondary prevention. The two large primary prevention trials, Prostate Cancer Prevention Trial/Seleninium and Vitamin E Chemoprevention Trial (PCPT/ SELECT), in low- and average-risk subjects have sample sizes of 18,000 to 32,000, with a treatment duration of 7 years to detect a 25% reduction in biopsy-proven PCa. Subjects with HGPIN have the highest known cancer risk (approximately 50% at 3 years), and thus require a small sample size (n = 450) to detect a 33% reduction in cancer incidence. A schema involving three sequential trials for agent registration is described. In summary, a CP strategy that incorporates well-defined agents, clinical and validated SE, and high-risk cohorts defined by genetic and acquired risk factors in a series of well-designed randomized controlled trials provides an efficient pathway for evaluating and approving new agents for PCa prevention.
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PMID:Prostate cancer chemoprevention: Strategies for designing efficient clinical trials. 1129 33

Polymorphism of the steroid hormone-related genes might affect life-long androgen exposure, thus altering a risk of prostate cancer incidence. To evaluate the effect of the polymorphisms of CYP17 and SRD5A2 on serum steroid hormone levels, the 164 male Japanese cohort were tested for serum hormone levels and the genotype of the polymorphisms of CYP17 (T-C base substitution in the promoter region) and SRD5A2 (V89L). The linear trends across the CYP17 genotypes in serum-free testosterone and androstenedione levels were found, suggesting the importance of the polymorphism of CYP17 in determining the circulating androgen levels.
Prostate Cancer Prostatic Dis 2004
PMID:Serum sex steroid hormone levels and polymorphisms of CYP17 and SRD5A2: implication for prostate cancer risk. 1547 77

We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men.
Prostate Cancer Prostatic Dis 2005
PMID:Association between hormonal genetic polymorphisms and early-onset prostate cancer. 1571 6

Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N = 4720), testosterone (N = 4678), 3 alpha-androstanediol-glucuronide (N = 4767) and 17beta-estradiol (N = 2014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (P = 4.52 x 10(-21)), consistent with previous studies, and testosterone (P = 7.54 x 10(-15)), with mean difference of 26.9 and 14.3%, respectively, comparing wild-type to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference = 8.8%, P = 7.37 x 10(-6)) and SRD5A2 with 3 alpha-androstanediol-glucuronide (rs2208532, mean difference = 11.8%, P = 1.82 x 10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones.
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PMID:Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3). 1957 43

Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.
Prostate Cancer 2012
PMID:Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men. 2309 30