Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma, but the frequency and timing of epigenetic changes found in prostate carcinogenesis has not been extensively documented. Thus, the promoters of three genes (APC, GSTP1, and RARbeta2) involved in prostate carcinogenesis were tested by quantitative methylation-specific PCR in tissue DNA from 30 prostate carcinomas, 128 high-grade PIN lesions, and 30 normal prostate tissue samples dissected from 30 radical prostatectomy specimens using laser capture microdissection. The percentage of methylated alleles (PMA) was calculated for each gene, and hierarchical cluster analysis was used to define the degree of similarity of epigenetic alterations among the various samples. We found that PMA values of APC and RARbeta2 were higher than those of GSTP1 in all three types of tissue samples and median PMA values for all three genes were higher in prostate cancer. By cluster analysis, 26 of 30 prostate carcinomas and 82 of 128 high-grade PIN lesions were grouped in the "high methylation" branch, whereas 24 of 30 normal prostate tissue samples were allocated in the "low methylation" branch. Although high-grade PIN lesions are epigenetically more similar to prostate carcinoma than to normal prostate tissue, paired prostate carcinoma and high-grade PIN lesions did not always segregate together. We concluded that APC and RARbeta2 hypermethylation is frequent in normal prostate tissue and the progressive enrichment in cells carrying methylated alleles observed in high-grade PIN and prostate carcinoma is consistent with clonal progression. Because GSTP1 promoter methylation is mainly observed in prostate carcinoma and some high-grade PIN lesions, it represents an important marker for the transition of in situ to invasive neoplasia.
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PMID:Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis. 1644 1

The kin-cohort design has been proposed as an alternative to traditional case-control and cohort measures to evaluate inherited susceptibility to cancer in population-based studies. Here, we used this design to evaluate inherited susceptibility to prostate cancer associated with APC I1307K using data from the Molecular Epidemiology of Colorectal Cancer study. Two techniques were used to compare the incidence of prostate cancer in APC I1307K carriers. First, we compared the incidence of prostate cancer in relatives of mutation carriers and noncarriers using standard techniques for survival analysis. Second, we used the marginal maximum likelihood method for kin-cohort analysis to infer the genotypes in the relatives. We also evaluated APC I1307K in 75 Ashkenazi Jewish individuals with prostate cancer from 27 families enrolled in the University of Michigan Prostate Cancer Genetic Study. We observed a slightly increased risk of prostate cancer in relatives of APC I1307K carriers, however, this difference was not statistically significant (hazard ratio, 1.6; 95% confidence intervals, 0.7-3.4). Similar conclusions were drawn using both techniques for kin-cohort analysis. APC I1307K was found in 7.4% of families genotyped, which is slightly higher than the allele prevalence reported in Ashkenazi Jews in the general population. In addition, we did not observe loss of heterozygosity at APC or a somatic mutation near APC I1307K using microdissected tumor DNA from mutation carriers enrolled in the Prostate Cancer Genetic Study. Overall, the evidence for an association between APC I1307K and prostate cancer is not compelling. APC I1307K is unlikely to play a clinically meaningful role in susceptibility to prostate cancer.
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PMID:APC I1307K and the risk of prostate cancer. 1653 3

Sipuleucel-T [APC 8015, Provenge] is an autologous, dendritic cell-based vaccine under development with Dendreon Corporation for the treatment of androgen-independent and androgen-dependent prostate cancer. It was generated using the company's active immunotherapy platform to stimulate a patient's own immune system to specifically target and destroy cancer cells, while leaving healthy cells unharmed. This approach could provide patients with a meaningful survival benefit and an improved tolerability profile over existing anticancer therapies. Sipuleucel-T selectively targets the prostate-specific antigen (PSA) known as prostatic acid phosphatase (PAP) that is expressed in approximately 95% of prostate cancers. It is produced by ex vivo exposure of dendritic cell precursors to PA 2024, a recombinant fusion protein composed of the PAP target fused to granulocyte-macrophage colony-stimulating factor (GM-CSF) and incorporated into Dendreon's proprietary Antigen Delivery Cassette. Patients are typically administered three intravenous (IV)-infusions of the vaccine over a 1-month period as a complete course of therapy. It is undergoing late-stage clinical evaluation among patients with early and advanced prostate cancer. In November 2003, Kirin Brewery returned to Dendreon the full rights to Sipuleucel-T for Asia. In exchange, Dendreon licensed patent rights relating to the use of certain HLA-DR antibodies to Kirin for $US20 million. This amended agreement enables Dendreon to complete ongoing discussions for a worldwide marketing and sales partnership for Sipuleucel-T. Similarly, Kirin is able to develop its HLA-DR monoclonal antibodies free of potential infringement claims arising from Dendreon's patent rights to HLA-DR. The licensing agreement relates to patent rights owned by Dendreon relating to monoclonal antibodies against the HLA-DR antigen. In addition, Dendreon retains rights to develop and commercialise its two existing HLA-DR monoclonal antibodies, DN 1921 and DN 1924, as well as other HLA-DR antibodies not being developed by Kirin. Previously, in May 1999, Dendreon and Kirin established a collaboration for the development of dendritic cell-based immunotherapeutics for cancer, including Sipuleucel-T. Under the agreement, Kirin would provide financial support for Dendreon's research on dendritic cells focused on developing immunotherapies for cancers most prevalent in Asia. Dendreon would retain US rights to products arising from the collaboration while Kirin would hold the rights to such immuno-therapeutics in Asia and Oceania. In August 2005, Dendreon signed an agreement to lease a commercial manufacturing facility in Hanover, New Jersey, USA. The company intends to develop the facility to meet anticipated clinical and commercial demands of Sipuleucel-T as well as other active immunotherapy product candidates. Dendreon and Diosynth Biotechnology (Akzo Nobel) have an agreement for the commercial production of the PA 2024 antigen component of Sipuleucel-T. In November 2003, Dendreon announced that Diosynth successfully manufactured PA 2024 on a commercial scale. In October 2001, Dendreon announced that Gambro Healthcare Inc. would provide a network of centres for cell collection to support commercial production and clinical development of various Dendreon vaccines, including Sipuleucel-T. Dendreon has outsourced its cell processing operations in Mountain View, California, USA to Progenitor Cell Therapy under an amended agreement signed in August 2002. This agreement is an expansion of an existing agreement, under which Progenitor provided Dendreon with cell-processing services through its facility in Hackensack, New Jersey, USA. The pivotal, two-stage, phase III trial (D9902 study) has been initiated at clinical sites in the US. The first stage of the trial (D9902A study) is a double-blind, placebo-controlled phase III trial designed to evaluate Sipuleucel-T in men with asymptomatic, metastatic, androgen-independent prostate cancer. The trial was originally designed to be the companion study to a previously completed phase III trial, called D9901. However, the D9902A study with 98 patients recruited was halted in December 2002, when analysis of the D9901 study revealed no statistically significant benefit in time to disease progression in the overall group, although a benefit was seen in a subgroup of patients with Gleason scores of < or =7. In April 2002, the US FDA requested clarification regarding cellular composition of Sipuleucel-T and the suspension of additional patient enrollment for the D9902 study; the request was related solely to manufacturing issues without patient safety being an issue. Trial enrollment resumed in October 2002 following FDA authorisation. Dendreon amended the protocol for the D9902 study and is only recruiting patients with asymptomatic, metastatic, androgen-independent prostate cancer, regardless of their Gleason Score (D9902B study). The ongoing pivotal phase III trial underwent a Special Protocol Assessment (SPA) with the FDA in August 2003 and is enrolling approximately 500 patients. The primary endpoint is overall survival with time to objective disease progression being a secondary endpoint. Final 3-year survival analysis of the D9902A study has been completed and presented. Previously, Dendreon completed an earlier phase III trial (D9901 study) that assessed Sipuleucel-T among 127 patients with late-stage, metastatic, hormone-independent prostate cancer in the US. All subjects had undergone surgical resection of the prostate, but had rising levels of PSA. Final 3-year survival data have been reported. Dendreon also conducted a phase II trial, known as D9905, that investigated Sipuleucel-T monotherapy among patients with early-stage prostate cancer. Study findings have been reported. In September 2003, the FDA designated Sipuleucel-T as a fast-track development programme for the treatment of asymptomatic, metastatic, androgen-independent prostate cancer. Subsequently, the FDA granted fast-track status to the vaccine in November 2005. Dendreon announced in September 1999 that a phase I trial of Sipuleucel-T in patients with prostate cancer had commenced in Japan. This study was being conducted at a dendritic cell processing centre that was formed as part of Dendreon's collaboration with Kirin. In addition, the US NCI is conducting a phase II trial (P-16) of Sipuleucel-T in combination with bevacizumab among patients with hormone-dependent prostate cancer. Trial results have been announced. In April 2001, Dendreon was awarded a US patent (No. 6,210,662) covering the composition of Sipuleucel-T. Dendreon acquired an exclusive worldwide licence to dendritic cell therapy for cancers and other diseases from the Immune Response Corporation; Immune Response originally received the exclusive patent rights to the technology from the University of Brussels in Belgium.
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PMID:Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine--Dendreon. 1675 45

In urothelial cancer, hypermethylation of specific genes and genome-wide hypomethylation, reflected in decreased methylation of LINE-1 retrotransposons, have both been reported, but were never investigated in the same specimens. We analyzed hypermethylation of six genes by methylation-specific PCR and LINE-1 hypomethylation by Southern blotting in 96 carcinoma tissues. Hypermethylation frequencies were: SFRP1 (55%), APC (45%), RASSF1A (35%), DAPK1 (29%), RARB2 (19%), and CDKN2A (2%). Three groups of cancers could be discerned, with escalating hypermethylation. Hypermethylation increased with tumor stage, particularly at the transition to invasive cancers, and RARB2 hypermethylation was indicative of lymph node involvement. A comparison to a previous study on prostate cancer using the same techniques suggests that hypermethylation in urothelial carcinoma occurs in a random rather than coordinated manner. LINE-1 hypomethylation was present in 90% of specimens, largely independent of hypermethylation. Lack of hypomethylation indicated a significantly better clinical prognosis. Bisulfite sequencing of SFRP1 demonstrated dense or patchy hypermethylation in tumor tissues that likely accounts for discrepant reported frequencies. In urothelial carcinoma cell lines, the same genes as in tissues were frequently hypermethylated. SFRP1 hypermethylation was concordant with lack of expression. 5-Aza-deoxycytidine induced its reexpression in some lines, whereas additional treatment with a histone deacetylase inhibitor was required in others. Thus, epigenetic SFRP1 inactivation occurs in a graduated manner. In conclusion, markers of genome-wide hypomethylation seem optimally suited for urothelial carcinoma detection, whereas combinations of hypermethylation and hypomethylation assays hold promise for classification.
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PMID:DNA methylation alterations in urothelial carcinoma. 1677 27

Prostate cancer is a highly prevalent malignancy, which is clinically silent but curable while organ-confined. Because available screening methods show poor sensitivity and specificity, the development of new molecular markers is warranted. Epigenetic alterations, mainly promoter hypermethylation of cancer-related genes, are common events in prostate cancer and might be used as cancer biomarkers. Moreover, the development of quantitative, high-throughput techniques to assess promoter methylation enabled the simultaneous screening of multiple clinical samples. From the numerous cancer-related genes hypermethylated in prostate cancer only a few proved to be strong candidates to become routine biomarkers. This small set of genes includes GSTP1, APC, RARbeta2, Cyclin D2, MDR1, and PTGS2. Single and/or multigene analyses demonstrated the feasibility of detecting early prostate cancer, with high sensitivity and specificity, in body fluids (serum, plasma, urine, and ejaculates) and tissue samples. In addition, quantitative hypermethylation of several genes has been associated with clinicopathologic features of tumor aggressiveness, and also reported as independent prognostic factor for relapse. The identification of age-related methylation at specific loci and the differential frequency of methylation among ethnical groups, also provided interesting data linking methylation and prostate cancer risk. Although large trials are needed to validate these findings, the clinical use of these markers might be envisaged for the near future.
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PMID:Epigenetic markers for molecular detection of prostate cancer. 1732 24

Diallyl trisulfide (DATS), a cancer chemopreventive constituent of garlic, inhibits growth of cancer cells by interfering with cell cycle progression, but the mechanism is not fully understood. Here, we show the existence of a novel ataxia-telangiectasia mutated and Rad3 related (ATR)/checkpoint kinase 1 (Chk1)-dependent checkpoint partially responsible for DATS-mediated prometaphase arrest in cancer cells, which is different from the recently described gamma irradiation-induced mitotic exit checkpoint. The PC-3 human prostate cancer cells synchronized in prometaphase by nocodazole treatment and released to DATS-containing medium remained arrested in prometaphase, whereas the cells released to normal medium exited mitosis and resumed cell cycle. The mitotic arrest was maintained even after 4 h of culture of DATS-treated cells (4-h treatment) in drug-free medium. The DATS-arrested mitotic cells exhibited accumulation of anaphase-promoting complex/cyclosome (APC/C) substrates cyclin A and cyclin B1 and hyperphosphorylation of securin, which was accompanied by increased phosphorylation of the APC/C regulatory subunits Cdc20 and Cdh1. The DATS-mediated accumulation of cyclin B1 and hyperphosphorylation of securin, Cdc20, and Cdh1 were partially but markedly attenuated by knockdown of Chk1 or ATR protein. The U2OS osteosarcoma cells expressing doxycycline-inducible kinase dead ATR were significantly more resistant not only to DATS-mediated prometaphase arrest but also to the accumulation of cyclin B1 and hyperphosphorylation of securin, Cdc20, and Cdh1 compared with cells expressing wild-type ATR. However, securin protein knockdown failed to rescue cells from DATS-induced prometaphase arrest. In conclusion, the present study describes a novel signaling pathway involving ATR/Chk1 in the regulation of DATS-induced prometaphase arrest.
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PMID:Activation of a novel ataxia-telangiectasia mutated and Rad3 related/checkpoint kinase 1-dependent prometaphase checkpoint in cancer cells by diallyl trisulfide, a promising cancer chemopreventive constituent of processed garlic. 1740 33

Promoter hypermethylation of circulating cell DNA has been advocated as a diagnostic marker for prostate cancer, but its prognostic use is currently unclear. To assess this role, we compared hypermethylation of circulating cell DNA from prostate cancer patients with (Group 1, n = 20) and without (Group 2, n = 22) disease progression and age-matched controls (benign prostatic hyperplasia, Group 3, n = 22). We measured hypermethylation of 10 gene promoters in 2 sequential venous samples, obtained at diagnosis and during disease progression (median time, 15 months later). Matched time samples were obtained in the nonprogressing patients. We found that more hypermethylation was detected in the diagnostic sample from the patients with cancer than in controls for GSTP1, RASSF1 alpha, APC and RAR beta (p < 0.0001). Patients undergoing disease progression had a significant increase in methylation levels of these 4 genes when compared to the other patients (p < 0.001). Patients at risk of disease progression have higher detectable concentrations of circulating cell hypermethylation, than those without progression. The extent of this hypermethylation increases during disease progression and can be used to identify the extent and duration of treatment response in prostate cancer.
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PMID:Promoter hypermethylation in circulating blood cells identifies prostate cancer progression. 1796 Jun 17

Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising. Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.
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PMID:Prostate cancer vaccines: current status and future potential. 1834 5

Patients with cancer have deficiencies in the number and function of dendritic cells. Loaded dendritic cell therapies attempt to overcome these deficiencies by exposing antigen-presenting cells to antigens ex vivo. Sipuleucel-T (APC-8015) is a novel immunotherapeutic consisting of autologous dendritic cells which have been pulsed ex vivo with PA2024 as a source of antigen. PA2024 is a recombinant fusion protein consisting of granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase. One phase III randomized clinical trial has demonstrated a survival benefit in patients with metastatic hormone-refractory prostate cancer, but additional information is needed before FDA approval. This review summarizes the clinical trials evaluating sipuleucel-T and discusses its potential role in the treatment of prostate cancer.
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PMID:Sipuleucel-T for the treatment of prostate cancer. 1853 85

The polycomb proteins BMI-1, EZH2, and SIRT1 are characteristic components of the PRC1, PRC2, and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate cancer progression, whereas BMI-1 and SIRT1 are not well investigated. Like EZH2 expression, DNA methylation alterations escalate in higher stage prostate cancers, raising the question whether these epigenetic changes are related. Expression of EZH2, BMI-1, SIRT1, and the DNA methyltransferases DNMT1 and DNMT3B measured by qRT-PCR in 47 primary prostate cancers was compared to APC, ASC, GSTP1, RARB2, and RASSF1A hypermethylation and LINE-1 hypomethylation. SIRT1 and DNMT3B were overexpressed in cancerous over benign tissues, whereas BMI-1 was rather downregulated and DNMT1 significantly diminished. Nevertheless, cancers with higher DNMT1 and BMI-1 expression had worse clinical characteristics, as did those with elevated EZH2. In particular, above median DNMT1 expression predicted a worse prognosis. EZH2 and SIRT1 overexpression were well correlated with increased MKI67. Immunohistochemistry confirmed limited EZH2 and heterogeneous DNMT3B overexpression and explained the decrease in BMI-1 by pronounced heterogeneity among tumor cells. EZH2 overexpression, specifically among all factors investigated, was associated with more frequent hypermethylation, in particular of GSTP1 and RARB2, and also with LINE-1 hypomethylation. Our data reveal complex changes in the composition of polycomb repressor complexes in prostate cancer. Heterogeneously expressed BMI-1 and slightly increased EZH2 may characterize less malignant cancers, whereas more aggressive cases express both at higher levels. SIRT1 appears to be generally increased in prostate cancers. Intriguingly, our data suggest a direct influence of increased EZH2 on altered DNA methylation patterns in prostate cancer.
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PMID:Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. 1863 71


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