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)

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n=48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.
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PMID:Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. 1933 69

To estimate the prostate cancer risk conferred by individual single nucleotide polymorphisms (SNPs), SNP-SNP interactions, and/or cumulative SNP effects, we evaluated the association between prostate cancer risk and the genetic variants of 12 key genes within the steroid hormone pathway (CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1). A total of 116 tagged SNPs covering the group of genes were analyzed in 2,452 samples (886 cases and 1,566 controls) in three ethnic/racial groups. Several SNPs within CYP19 were significantly associated with prostate cancer in all three ethnicities (P = 0.001-0.009). Genetic variants within HSD3B2 and CYP24A1 conferred increased risk of prostate cancer in non-Hispanic or Hispanic Caucasians. A significant gene-dosage effect for increasing numbers of potential high-risk genotypes was found in non-Hispanic and Hispanic Caucasians. Higher-order interactions showed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = 0.001). In African Americans, a 10-locus model, with SNPs located within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1, showed a significant interaction (P = 0.014). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < 0.001). These data are consistent with a polygenic model of prostate cancer, indicating that multiple interacting genes of the steroid hormone pathway confer increased risk of prostate cancer.
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PMID:Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. 1950 20

Abiraterone acetate is a potent, selective, and orally bioavailable small molecule inhibitor of CYP17, an enzyme that catalyzes two key serial reactions (17 alpha hydroxylase and 17,20 lyase) in androgen and estrogen biosynthesis. Clinical trials have confirmed that specific inhibition of CYP17 is safe and results in clinically important antitumor activity in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. These clinical data indicate that castration-resistant prostate cancer frequently remains hormone dependent and has confirmed that this disease should no longer be described as "hormone resistant or refractory". Biomarker studies, including the analysis of ETS gene fusion status, on patients treated with abiraterone acetate may allow enrichment of patients with a sensitive phenotype in future studies of therapeutics targeting CYP17.
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PMID:Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. 1950 32

Prostate cancer is a major cause of cancer-related death in men. Prostate cancer is an androgen-responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy. First-line treatment for advanced prostate cancer is androgen deprivation therapy (ADT), usually with agents that suppress gonadotropins through a pituitary mechanism. Gonadotropin-releasing hormone agonists and antagonists both suppress gonadal release of testosterone, although their activity profiles vary. ADT down-regulates androgen receptor (AR) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration-resistant prostate cancer (CRPC). Although serum testosterone concentrations decline dramatically with ADT, CRPC growth remains largely dependent on AR activity. Secondary hormonal therapies are then often employed to further dampen AR-driven transcription. These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis, or directly and competitively antagonize AR. New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC. Abiraterone acetate is an inhibitor of CYP17, which is an enzyme required for the synthesis of all androgens and estrogens. MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use. In phase I and phase II clinical trials, both agents have significant activity. These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients, which will improve clinical outcomes.
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PMID:Hormonal therapy for prostate cancer: toward further unraveling of androgen receptor function. 1971 56

In castrate-resistant prostate cancer, beyond chemotherapy, existing guidelines suggest only supportive care. However, recent evidence suggests that continued targeting of androgen-dependent pathways may be an efficacious approach. Clinical data is now available for two mechanistically distinct agents (abiraterone and MDV3100) that both ultimately target these pathways. Abiraterone is a potent and irreversible inhibitor of CYP17, a critical enzyme in androgen biosynthesis. Phase II studies indicate substantial declines in PSA amongst castrate-resistant patients treated with abiraterone, both prior to and following cytotoxic chemotherapy. In contrast to abiraterone, MDV3100 is a direct inhibitor of the androgen receptor, binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide. A recent phase I/II trial of MDV3100 in castrate-resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level. On the basis of these compelling data, both abiraterone and MDV3100 will be examined in the phase III setting.
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PMID:Beyond castration and chemotherapy: novel approaches to targeting androgen-driven pathways. 1973 87

African American (AA) men with prostate cancer (PCa) have worse disease, with a higher incidence, younger age and more advanced disease at diagnosis, and a worse prognosis, compared to Caucasian (CA) men. In addition to socioeconomic factors and lifestyle differences, molecular alterations contribute to this discrepancy. In this review, we summarize molecular genetics research results interrelated with the biology of PCa racial disparity. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of the genes of the enzymes involved in androgen biosynthesis and metabolism, such as SRD5A2, CYP17, and CYP3A4. The levels of expression and CAG repeat length of AR also show racial divergence and may be critical molecular alterations for racial disparity. Growth factors and their receptors, which promote cancer cell growth, are another potential cause of the disparity; both EGFR and EPHB2, two of the most studied receptors, show interethnic differences. Differences have also been found among genes regulating cell apoptosis, such as BCL2, which is increased in PCa in the AA population. Recent developments in genetics, proteomics, and genomics, among other molecular biotechnologies, will greatly aid the advancement of translational research on PCa racial disparity, hopefully culminating in the discovery of novel mechanisms of disease, in addition to prognostic markers and novel therapeutic approaches.
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PMID:Molecular mechanisms involving prostate cancer racial disparity. 1995 34

Genetic polymorphisms described for a number of enzymes involved in the metabolism of tobacco carcinogens and alcohol have been linked to increase cancer risk. Racial disparities in cancer between whites and populations of African descent are well documented. In addition to differences in access to health care, both environment and genetic factors and their interaction may contribute to the increased cancer risk in minority populations. We reviewed the literature to identify case-control studies that included subjects of African descent. Meta-analyses investigating the association of genetic polymorphisms in tobacco metabolic genes and cancer were performed. Although several genes and cancers have been studied, only one or two studies per gene for each cancer site have been published, with the exception of breast (CYP1A1 and CYP1B1), lung (GSTM1, CYP1A1, and NQO1), and prostate (CYP3A4 A293G and CYP17). Marginal statistically significant associations were observed for CYP3A4 A293G and CYP17 5'UTR polymorphisms and prostate cancer. Our findings support the need for additional genetic association studies of breast, prostate, and lung cancers that include a larger number of minority participants. Because incidence and mortality rates for these cancers rank highest among populations of African descent, concentrated research in these areas are warranted.
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PMID:Review of studies on metabolic genes and cancer in populations of African descent. 2002 11

The aim of the paper is to determine whether IGF1, IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and one-nucleotide polymorphism in PSA and CYP17 gene might contribute to early diagnostics of prostate cancer (PCa). Serum level of PSA, IGF1 and IGFBP3 in the group of 158 individuals (92 PCa and 66 controls) was examined by RIA method and IGF1/IGFBP3 was calculated. PCR RLFP method was used to examine one- nucleotide polymorphism in PSA and CYP 17 gene. The results suggest that serum level of IGF1 over 95% CI did not increase relative risk of PCa development in overall group, not even regarding to particular investigated genotypes, not even if individuals with genotype AG+A1A1, AG+A1A2, GG+A1A1 and GG+A1A2 were evaluated. Serum level of IGFBP3 under 95% CI increased PCa relative risk in overall group(chi(2) = 10,03, p= 0,001, OR 3,12, 95% CI 1,44-6,93), as well as regarding to one-nucleotide polymorphism in individuals with PSA genotype AG(chi(2) = 4,72 p= 0,029, OR 2,87, 95% CI 01,09-7,49) and CYP 17 genotype A1A1(chi(2) = 3,76 p= 0,052, OR 2,57, 95% CI 0,97-6,75). The association between frequencies of occurrence of PCa and higher IGF1/IGFBP3 molar ratio was not confirmed, nor for gene polymorphism in PSA and CYP17, however OR (chi(2) = 1,58, p= 0,208, OR 1,67, 95% CI 0,75-3,71) was more than 1, nor in combination AG+A1A1,AG+ A1A2. Serum level of IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and gene polymorphism in PSA and CYP17 gene might contribute to early diagnostics of PCa. Further research is needed to prove, whether serum level of IGFBP3 in addition to PSA determines the prognosis and progression of PCa.
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PMID:Serum level of IGFBP3 and IGF1/IGFBP3 molar ratio in addition to PSA and single nucleotide polymorphism in PSA and CYP17 gene may contribute to early diagnostics of prostate cancer. 2009 74

The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed.
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PMID:Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. 2023 42

Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.
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PMID:Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer. 2046 82


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