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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases is part of a network of pathways that are involved in the development and progression of prostate cancer. HER-kinase receptors include epidermal growth factor receptor (EGFR), HER2, HER3, and HER4, which must combine as dimers to affect signaling. Different combinations of receptors produce different qualities and levels of pathway activation. Among HER-family receptors, HER2 activation is particularly important in breast cancer, as HER2 gene amplification is associated with a distinct clinical course and response to treatment with a HER2-directed therapy (trastuzumab). Although HER2 can be over-expressed in prostate cancer, there is no clinical data to support the use of trastuzumab for prostate cancer patients. Preclinical and clinical data show that the activation of the HER-kinase axis is important for the progression of prostate cancer to androgen-independent disease. Data points towards the importance of inhibiting multiple members of the HER-kinase family to achieve more complete blockade of this axis for cancers other than HER2-overexpressing breast cancer. Multiple pharmaceutical agents that block the HER-kinase axis are currently being tested for patients with prostate cancer. These include antibodies, tyrosine kinase inhibitors, and novel strategies which seek to decrease HER2 expression.
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PMID:Update on HER-kinase-directed therapy in prostate cancer. 1616 60

Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen-dependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasome-mediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer.
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PMID:Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. 1617 22

Human prostatic acid phosphatase (PAcP) was used as a valuable surrogate marker for monitoring prostate cancer prior to the availability of prostate-specific antigen (PSA). Even though the level of PAcP is increased in the circulation of prostate cancer patients, its intracellular level and activity are greatly diminished in prostate cancer cells. Recent advances in understanding the function of the cellular form of PAcP (cPAcP) have shed some light on its role in prostate carcinogenesis, which may have potential applications for prostate cancer therapy. It is now evident that cPAcP functions as a neutral protein tyrosine phosphatase (PTP) in prostate cancer cells and dephosphorylates HER-2/ErbB-2/Neu (HER-2: human epidermal growth factor receptor-2) at the phosphotyrosine (p-Tyr) residues. Dephosphorylation of HER-2 at its p-Tyr residues results in the down-regulation of its specific activity, which leads to decreases in growth and tumorigenicity of those cancer cells. Conversely, decreased cPAcP expression correlates with hyperphosphorylation of HER-2 at tyrosine residues and activation of downstream extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling, which results in prostate cancer progression as well as androgen-independent growth of prostate cancer cells. These in vitro results on the effect of cPAcP on androgen-independent growth of prostate cancer cells corroborate the clinical findings that cPAcP level is greatly decreased in advanced prostate cancer and provide insights into one of the molecular mechanisms involved in prostate cancer progression. Results from experiments using xenograft animal models further indicate a novel role of cPAcP as a tumor suppressor. Future studies are warranted to clarify the use of cPAcP as a therapeutic agent in human prostate cancer patients.
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PMID:Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. 1632 23

Cancer cells frequently exhibit a significant increase in overexpression and activity of fatty acid synthase (FASN). Elevated FASN pathway activity also occurs in prostate cancer, the second leading cause of cancer-related death in men in the United States. Studies show that genes associated with an increase in protein expression, such as HER2/neu in breast cancer, are associated with an increase in gene copy number as well as an increase in transcription. In the present study, we evaluated whether FASN follows a similar paradigm in prostate cancer. To date, elevated FASN expression in prostate cancer has not been correlated with gene copy number alterations. Using immunohistochemistry and fluorescence in situ hybridization analysis in paraffin-embedded tissue microarrays, we observed gene copy gain in 24% of all prostate adenocarcinoma specimens examined with concurrent increased FASN protein expression. Immunohistochemistry alone showed 59% of prostate cancer specimens in the same tissue microarray with high FASN expression. Increased FASN gene was observed in 53% of all prostate tissues expressing elevated FASN protein levels and in 2 of 5 prostate tumor cell lines tested. These findings suggest that FASN gene copy number increases may be involved in the resultant increase in FASN protein expression observed in prostatic disease.
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PMID:Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. 1656 13

Huggins and Hodges described the first systemic targeted therapy for prostate cancer in 1941 with their report on the effects of androgen ablation in men with metastatic disease. Since that time, researchers have identified multiple additional "targets" that may be important in prostate cancer tumorigenesis. These areas include continued emphasis on the androgen receptor in the androgen-independent state, parallel growth pathways such as AKT and HER2 that may act in conjunction or independently of the androgen receptor, the supporting environment that allows for the development of metastatic disease, and standard cytotoxic targets, such as the microtubule. This review is intended to highlight these potential targets and several of the agents that are under development in the treatment of prostate cancer.
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PMID:Targeted approaches for the management of metastatic prostate cancer. 1661 85

Previous studies have demonstrated HER2 protein overexpression and/or gene amplification in a subset of patients with clinically significant prostate cancer (PCa), especially in the androgen-independent phase of the disease. There are no studies on incidentally detected PCa. The aim of the study was to analyze HER2 expression and gene amplification in PCa incidentally detected in cystoprostatectomies. High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. Comparison was made with clinically detected PCa, both untreated and hormonally treated, and with androgen-independent PCa. Nineteen cystoprostatectomy (CyP) and 44 radical prostatectomy specimens (25 untreated and 19 hormonally treated) with pT2a Gleason score 6 cancer and HGPIN were used in this study. It also included 9 specimens of transurethral resection of the prostate with hormone-independent cancer and 8 cases of normal prostate tissue from CyP specimens without PCa and prostatic intraepithelial neoplasia. HER2 protein and Ki-67 were investigated immunohistochemically. Patients with immunohistochemical scores of 2+ and 3+ were considered to have HER2 overexpression (HercepTest method). Dual-color fluorescence in situ hybridization analysis was performed using the CEP-17/HER dual probe combination. High-grade prostatic intraepithelial neoplasia showed HER2 overexpression in 26% of the CyP cases and in 40% and 83% of the untreated and treated cases, respectively. Prostate cancer showed HER2 overexpression in 16% of cases in the CyP group and in 36% and 47.5% in the untreated and treated groups, respectively. HER2 overexpression was present in 78% of androgen-independent cancers. HER2 gene amplification was seen in a small proportion of nuclei and some of the cases. In HGPIN, it ranged from 1.1% (in 5 cases) in the CyP group to 2.1% (in 10 cases) and 1.9% (in 6 cases) in the untreated and treated groups, respectively. In PCa, the proportion of nuclei with gene amplification was 0.7% (in 3 cases) in the CyP group, 2.6% (in 10 cases) and 2.5% (in 12 cases) in the untreated and treated groups, respectively, and 9% (in 6 cases) in the androgen-independent PCa. Ki-67 expression in HGPIN and PCa in CyP specimens was lower than in the radical prostatectomies and cases of transurethral resection of the prostate. Our findings in the current HER2-related study indicate that incidentally detected cancer has features of less aggressiveness than clinically detected cancer. This may contribute to a better understanding of the results obtained in screening programs where insignificant cancers are detected along with clinically significant cancers.
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PMID:HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent cancer. 1693 18

Present management of metastatic prostate cancer, which includes hormonal therapy, chemotherapy, and radiotherapy, are frequently palliative. Taxanes, and specifically docetaxel, are being extensively investigated to improve the survival of metastatic prostate cancer patients. Although paclitaxel exhibits a wide spectrum of antitumor activity, its therapeutic application is limited, in part, due to its low water solubility that necessitates the use of Cremophor EL, which is known to induce hypersensitivity reactions. Therefore, the objective of this present study was to assess the efficiency of paclitaxel palmitate-loaded anti-HER2 immunoemulsions, a targeted drug delivery system based on cationic emulsion covalently linked to anti-HER2 monoclonal antibody (Herceptin), in a well-established in vivo pharmacologic model of metastatic prostate cancer that overexpresses the HER2 receptor. It was clearly noted that the cationic emulsion and immunoemulsion did not activate the complement compared with the commercial and paclitaxel palmitate hydroalcoholic formulations. In addition, 10 mg/kg of paclitaxel palmitate-loaded immunoemulsion once weekly over 3 weeks inhibits the tumor growth in severe combined immunodeficient mice much more than the cationic emulsion (P < 0.05) and the paclitaxel palmitate formulation (P < 0.01). The histopathologic analysis suggested a therapeutic improvement trend in favor of the immunoemulsion. However, there was no significant difference in antimetastatic activity between the emulsion and the immunoemulsion despite the affinity of the immunoemulsion towards the HER2 receptor. Although the tumor growth was not fully inhibited, the actual results are encouraging and may lead to an improved therapeutic strategy of metastatic prostate cancer treatment.
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PMID:Anti-HER2 cationic immunoemulsion as a potential targeted drug delivery system for the treatment of prostate cancer. 1721 Jul 7

Antitumour activity of docetaxel (Taxotere) in hormone-dependent (HD) and hormone-independent (HID) prostate cancer PAC120 xenograft model was previously reported, and its level was associated with HER2 protein expression. In the present study, we evaluate the antitumour effects of docetaxel combined with trastuzumab (Herceptin), an anti-HER2 antibody. Although trastuzumab alone had no effect on tumour growth, it potentiated the antitumour activity of docetaxel in HD tumours and more strongly in HID variants. Using the HID28 variant, we show that docetaxel treatment of tumour-bearing mice induces an increased HER2 mRNA expression of the tyrosine kinase receptor of 25-fold 24 h after docetaxel treatment, while HER2 protein and p-AKT decreased. This was followed by an increase of HER2 protein 3 days (two-fold) after docetaxel treatment and by a strong HER2 release in the serum of treated mice; expression of phospho-ERK, p27, BCL2 and HSP70 concomitantly increased. Similar molecular alterations were induced by docetaxel plus trastuzumab combination, except for that there was a transient and complete disappearance of AR and HSP90 proteins 24 h after treatment. We show that in addition to its known effects on tubulin and mitotic spindles, docetaxel induces complex signalisation pathway mechanisms in surviving cells, including HER2, which can be pharmacologically targeted. This study suggests that the docetaxel/trastuzumab combination may prove an effective therapeutic approach for HER2-expressing hormone-refractory prostate cancer.
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PMID:Potentiation of antitumour activity of docetaxel by combination with trastuzumab in a human prostate cancer xenograft model and underlying mechanisms. 1721 67

The aim of the current study was to analyze HER-2 expression and gene amplification in prostate cancer and HGPIN incidentally detected in cystoprostatectomies. Eighty prostate cases were used. Group 1 (incidental): nineteen cystoprostatectomy specimens with prostate cancer and HGPIN and no residual urothelial carcinoma in the prostate. Group 2 (untreated): twenty-five radical prostatectomy specimens with prostate cancer Group 3 (hormonally treated): nineteen radical prostatectomy specimens with prostate cancer. All the patients were under total androgen ablation therapy for three months before surgery. Group 4 (hormone-independent): nine TURP specimens with locally recurrent androgen independent prostate cancer Group 5 (normal reference): eight cystoprostatectomy specimens without HGPIN and without prostate cancer, and no residual urothelial carcinoma. None of the patients belonging to Groups 1, 2, and 5 had received chemotherapy, hormone therapy, or radiation therapy before surgery. Weak to moderate HER-2 membrane immunoreactivity was observed in most of the basal cells but not in the secretory cells of normal prostatic ducts and acini both in the cystoprostatectomies and in the radicals of the untreated patients. High-grade PIN. HER-2 overexpression was present in the secretory cells in 26% of HGPIN cases in the CyP group, 40% in the untreated clinically detected cancer group, and 83% in the treated group. Prostate cancer HER-2 overexpression was seen in 16% of cases in the CyP group, 36% in the untreated group and 47.5% in the treated group. HER-2 overexpression was present in 78% of cases with androgen independent PCa. Association of HER-2 overexpression and gene amplification. When considering HGPIN the lowest proportion of cases with HER-2 overexpression and with nuclei with gene amplification was seen in the CyP specimens (7%), whereas the highest was in the treated material (28%). As far as the cancers were concerned, the proportions were slightly higher than in HGPIN, the lowest value being in the CyP specimens (9%) and the highest in the hormone independent PCa (62.5%). A statistically significant difference in the number of cases with both overexpression and amplification was only seen between CyP and hormone-independent cancers (p = 0.007).
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PMID:HER-2 expression and gene amplification in high-grade PIN and prostate cancer. 1726 16

HER2 and TOP2A genes, located on 17q, can be coamplified in cancer. Overexpression of both genes has been reported in high-grade, androgen-resistant prostate cancer. Both genes have not been compared in a single prostate cancer study and the frequency of TOP2A amplifications in prostate cancer is unknown. Using tissue microarrays, we did immunohistochemistry and fluorescence in situ hybridization for HER2 and TOP2A in 100 prostate cancers (41 localized and 59 advanced) and 42 cases of benign prostatic hyperplasia (BPH). Amplification was defined as a target/centromere signal ratio of > or =1.5. HER2 immunohistochemistry was scored from 0 to 3+. Percentage nuclei staining for topoisomerase IIalpha (topoIIalpha) was recorded; overexpression was defined as > or =5% cells staining. Eighteen (31%) advanced prostate cancers showed topoIIalpha overexpression; 12 (26%) showed TOP2A low-level amplification; 9 (16%) expressed HER2; and 6 (13%) showed HER2 low-level amplification. No high-level amplification of either gene (target/centromere signal ratio of > or =3.0) was detected. TOP2A coexpression and coamplification were seen in 75% and 66% of HER2-positive cases, respectively. Localized prostate cancer or BPH showed no gene amplification or topoIIalpha overexpression. Gene amplification or overexpression correlated with high stage and Gleason score. The presence of TOP2A amplification in advanced cancer was associated with androgen resistance and decreased survival by multivariate analysis. This is the first study to document low-level TOP2A amplification in prostate cancer and an association with reduced survival. TOP2A amplification may occur with or without HER2 duplication and is often associated with topoIIalpha expression. Therapies directed against topoIIalpha (and HER2) in such patients may improve survival.
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PMID:Low-level TOP2A amplification in prostate cancer is associated with HER2 duplication, androgen resistance, and decreased survival. 1736 13


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