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)

The measurement of tumor markers is currently one of the most rapidly growing areas in laboratory medicine. Lack of sensitivity and specificity preclude the use of most existing markers for the early detection of malignancy. For patients with diagnosed malignancy, however, markers are potentially useful in determining prognosis, predicting therapeutic response, maintaining surveillance following curative surgery and monitoring therapy in advanced disease. Clinically useful markers include CEA in the surveillance of patients with diagnosed colorectal cancer, AFP and HCG in the management of patients with non-seminomatous germ cell tumors, HCG in the management of patients with trophoblastic disease, CA 125 for monitoring therapy in patients with ovarian cancer, estrogen receptors for predicting response to hormone therapy in breast cancer and HER-2 for the identification of women with breast cancer likely to respond to trastuzumab (Herceptin). Although widely used, the impact of PSA screening in reducing mortality from prostate cancer remains to be shown.
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PMID:Role of tumor markers in patients with solid cancers: A critical review. 1744 88

Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth of LNCaP and LAPC-4 prostate xenograft tumors, AR recruitment to the androgen-responsive enhancer, and androgen-inducible gene expression in the absence of androgen. Heregulin-stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation. Ack1 knockdown inhibited heregulin-dependent AR tyrosine phosphorylation, AR reporter activity, androgen-stimulated gene expression, and AR recruitment. Ack1 was recruited to the androgen-responsive enhancers after androgen and heregulin stimulation. In 8 of 18 primary androgen-independent prostate tumor samples, tyrosine-phosphorylated AR protein was detected and correlated with the detection of tyrosine-phosphorylated Ack1. Neither was elevated in androgen-dependent tumors or benign prostate samples. Activated Ack1 phosphorylated AR protein at Tyr-267 and Tyr-363, both located within the transactivation domain. Mutation of Tyr-267 completely abrogated and mutation of Tyr-363 reduced Ack1-induced AR reporter activation and recruitment of AR to the androgen-responsive enhancer. Expression of AR point mutants inhibited Ack1-driven xenograft tumor growth. Thus, Ack1 activated by surface signals or oncogenic mechanisms may directly enhance AR transcriptional function and promote androgen-independent progression of prostate cancer. Targeting the Ack1 kinase may be a potential therapeutic strategy in prostate cancer.
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PMID:Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. 1749 60

A humanized anti-HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent antitumor activity against HER2-expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti-tumor activity of pertuzumab against eight non-small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)-alpha. Pertuzumab significantly inhibited the HRG-alpha-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-alpha-stimulated phosphorylation of HER3, mitogen-activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)-stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG-alpha-stimulated HER2/HER3 heterodimer formation. HRG-alpha-stimulated HER3 phosphorylation was also observed in the PC-9 cells co-overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG-alpha nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling.
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PMID:Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. 1762 12

We investigated efficacy of gefitinib in hormone-refractory prostate cancer. Between March 2003 and December 2004, 23 patients with hormone-refractory prostate cancer were assigned to receive 250 mg oral gefitinib daily in addition to antiandrogen and luteinizing hormone-releasing hormone analogue for at least 2 months or until disease progression. Patients with progression stopped antiandrogen therapy, and received gefitinib and the luteinizing hormone-releasing hormone analogue. Serum HER2 and epidermal growth factor receptor extracellular domain were evaluated every 2 months. Gefitinib treatment did not result in any objective measurable response or responses in prostate-specific antigen. Median time to progression was 70 days (33-336). Median overall survival was 293 days (25-75 percentile: 235-349). HER2 extracellular domain mean value was 9.6 ng/ml (range 6.9-13.3) at basal time and was 10.1 (range 6.0-14.1) after 2 months. Epidermal growth factor receptor mean basal value was 51.0 ng/ml (range 41.4-75.3). After 2 months of treatment the mean value was 51.1 ng/ml (range 41.5-61.4). One patient had reduction in the pain score from baseline without an increase in the analgesic score. Four patients (17%) out of 23 had pain progression with an increase from baseline of at least 25% in the analgesic score. The study was discontinued before target accrual was reached owing to lack of efficacy of the drug. Our results do not support the efficacy of gefitinib in combination with endocrine treatment for hormone-refractory prostate cancer.
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PMID:Gefitinib combined with endocrine manipulation in patients with hormone-refractory prostate cancer: quality of life and surrogate markers of activity. 1766 1

Nanoparticles 100 nm in diameter containing indocyanine green (ICG) have been developed as a contrast agent for photoacoustic (PA) imaging based on (photonic explorers for biomedical use by biologically localized embedding PEBBLE) technology using organically modified silicate (ormosil) as a matrix. ICG is an FDA-approved dye with strong optical absorption in the near-infrared (NIR) region, where light can penetrate deepest into biological tissue. A photoacoustic imaging system was used to study image contrast as a function of PEBBLE concentration in phantom objects. ICG-embedded ormosil PEBBLEs showed improved stability in aqueous solution compared with free ICG dye. The particles were conjugated with HER-2 antibody for breast cancer and prostate cancer cell targeting. Initial in vitro characterization shows high contrast and high efficiency for binding to prostate cancer cells. ICG can also be used as a photosensitizer (generating toxic oxygen by illumination) for photodynamic therapy. We have measured the photosensitization capability of ICG-embedded ormosil nanoparticles. This feature can be utilized to combine detection and therapeutic functions in a single agent.
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PMID:Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging. 1786 24

Several monoclonal antibodies that target cell surface receptors have gained approval by the U.S. Food and Drug Administration and are widely used in the treatment of some cancers. These include but are not limited to the anti-CD20 antibody Rituximab, used in lymphoma treatment, as well as anti-HER-2 antibody for breast cancer therapy. The efficacy of this cancer immunotherapy modality is, however, limited by the large size of the antibody (160 kd) and its relatively nonspecific binding to the reticuloendothelial system. This latter property is particularly problematic if the antibody is used as a vehicle to deliver radionuclides, cytotoxic drugs, or toxins to the tumor site. Peptides, peptidomimetic, or small molecules are thus attractive as alternative cell surface targeting agents for cancer imaging and therapy. Cancer cell surface targeting peptides can be derived from known native peptide hormones such as somatostatin and bombesin, or they can be identified through screening combinatorial peptide libraries against unknown cell surface receptor targets. Phage-display peptide library and one-bead one-compound (OBOC) combinatorial library methods have been successfully used to discover peptides that target cancer cells or tumor blood vessel endothelial cells. The phage-display peptide library method, because of its biological nature, can only display l-amino acid peptides. In contrast, the OBOC combinatorial library method allows for bead-surface display of peptides that contain l-amino acids, d-amino acids, unnatural amino acids, or other organic moieties. We have successfully used the OBOC method to discover and optimize ligands against unique cell surface receptors of prostate cancer, T- and B-cell lymphoma, as well as ovarian and lung cancers, and we have used some of these peptides to image xenografts in nude mice with high specificity. Here, we (i) review the literature on the use of phage-display and OBOC combinatorial library methods to discover cancer and tumor blood vessel targeting ligands, and (ii) report on the use of an ovarian cancer targeting ligand, OA02, as an in vivo PET imaging probe in a xenograft model in nude mice.
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PMID:From combinatorial chemistry to cancer-targeting peptides. 1788 Jan 66

Receptors for vasoactive intestinal peptide (VIP) and the human epidermal growth factor family of tyrosine kinase receptors (HER) are potent promoters of cell proliferation, survival, migration, adhesion and differentiation in prostate cancer cell lines. In this study, we analyzed the cross-talk between both classes of receptors through the regulation of HER2 transactivation and expression by VIP. Three growth-hormone-releasing hormone analogs endowed with antagonistic activity for VIP receptors (JV-1-51, -52, and -53) abrogated the autocrine/paracrine stimuli of VIP on androgen-independent PC3 cells in the absence or the presence of 10% fetal bovine serum. Semiquantitative and real-time quantitative RT-PCR together with Western blotting showed increased expression levels of both mRNA and proteins for HER2 and HER3 in PC3 and androgen-dependent LNCaP prostate cancer cells as compared to non-neoplastic RWPE-1 cells. VIP (100 nM) stimulated the expression levels of both HER2 and HER3 in PC3 cells in a time-dependent manner. Whereas these effects were relatively slow, VIP rapidly (0.5 min) increased HER2 tyrosine phosphorylation. This pattern of HER transactivation was blocked by H89, a protein kinase A (PKA) inhibitor, as well as by the specific VIP antagonist JV-1-53, indicating the involvement of VIP receptors and PKA activity in phosphorylated HER2 formation. These findings support the merit of further studies on the potential usefulness of VIP receptor antagonists and both HER2 antibodies and tyrosine kinase inhibitors for prostate cancer therapy.
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PMID:Transactivation of HER2 by vasoactive intestinal peptide in experimental prostate cancer: Antagonistic action of an analog of growth-hormone-releasing hormone. 1791 51

Interferon-gamma (IFN-gamma) is known to downregulate HER2 oncoprotein (p185(HER2) or briefly p185) in prostate cancer cells. We demonstrate that the IFN-gamma-induced retinoid-inducible gene 1 (RIG1) acts as a transrepressor of p185. Furthermore, we exhibit that RIG1 downregulates the activated (phosphorylated) form of p185 and phosphoinositide-3 kinase (PI3K)/serine/threonine-specific protein kinase (Akt) and the mammalian target of rapamycin (mTOR), downstream substrates of HER2. We also elucidate that heregulin (HRG) specifically restores the activation of p185 and Akt after their activities are reduced by RIG1. Additionally, expression of vascular endothelial growth factor (VEGF) increases through the HER2- and Akt/mTOR-signaling pathways, indicating that VEGF is downregulated by RIG1 within the cell. These findings suggest that RIG1 plays a role in IFN-gamma-mediated therapy by downregulating p185 and its downstream PI3K/Akt/mTOR/VEGF-signaling pathway. These results may provide a new therapeutic mechanism for the clinical use of IFN-gamma and RIG1.
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PMID:Downregulation of HER2 by RIG1 involves the PI3K/Akt pathway in ovarian cancer cells. 1817 56

In an effort to improve affinity biomarker validation in fixed patient tissue specimens, we have developed a novel quantum dot-based bioimaging system that utilizes chicken IgY antibody for high sensitivity and specificity relative quantitation of cancer proteins. Monospecific, polyclonal IgYs were generated against human HER2 and telomerase, and analytically validated for specificity by western blot and immunohistochemistry on tumor and normal cells and for relative affinity by layered peptide array (LPA). IgYs bound desired targets in cell lines and fixed tissues and showed greater affinity than commercial mammalian antibodies for both HER2 and telomerase proteins. In tissue microarray experiments, HER2 quantitation with IgY antibody and quantum dot imaging correlated well with chromogenic in situ hybridization (CISH), whereas telomerase quantitation suggested a trend toward correlation with prostate cancer Gleason Grade and differentiation. Although patient numbers were small, these findings demonstrate the feasibility of relative quantitation of cancer biomarkers with IgY and quantum dot fluorophores, and show promise for rigorous clinical validation in large patient cohorts.
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PMID:Quantitation of HER2 and telomerase biomarkers in solid tumors with IgY antibodies and nanocrystal detection. 1821 59

At the 13th Oncology Forum, future directions of anticancer drug development in Japan were discussed. Development of anticancer drugs in the 1990s was based on the concept of total cell kill, but now development of molecular targeted drugs becomes the mainstream. Unfortunately, molecular targeted drugs and antibody agents are mostly foreign products and translational research in Japan is poor as it stands now. As future directions of anticancer drug development, international collaborative development is considered essential, but there are various obstacles to the conduct of international collaborative studies. Companies, medical institutions and regulatory agencies must make collaborative efforts to overcome these obstacles. As future development of anticancer agents in individual cancer regions in Japan is considered, gastric cancer therapy is progressing considerably with the advent of S-1 and in the future, development of multi-agent combination therapy including molecular targeted agents is expected. Much progress in colon cancer therapy has been made owing to accumulation of evidence in recent years. Multi-agent chemotherapy combined with antibody agent, which is advancing overseas, is introduced to Japan. Clinical development of combination therapy with a high therapeutic index, including compounds discovered in Japan, is expected in the future. Although conventionally hormone therapy has been considered as first-line treatment of breast cancer and used in combination with chemotherapy, with the advent of antibody agents in recent years, HER2 sensitivity has greatly affected the algorithm of treatment. Future development of molecular targeted drugs and individualised diagnosis using cDNA array, etc. are likely to advance individualisation of treatment. On the other hand, large-scale clinical trials are required to prove a small difference in adjuvant therapy, etc. and accordingly international studies are becoming indispensable. For urological cancers, molecular targeted drugs have been proved effective in renal cancer and future development of molecular targeted drugs for prostate cancer and testicular tumors is desirable. At that time, elucidation of the mechanism of action of molecular targeted drug and strategic drug development designed to increase its efficacy are expected. As a future direction of anticancer drug development, there are many cancers in whose international collaborative studies Japan can participate. Studies of prostate cancer and renal cell carcinoma can be internationalised while internationalisation of studies in ovarian and pancreatic cancers is essential. Phase III should be performed as international collaborative studies and depending on the type of cancer and drug, collaborative studies in an Asian region are effective. When participating in an international collaborative study, Japan needs to recruit subjects at a speed similar to the rest of the world, but differences in medical environment including clinical trials pose a problem. To solve this problem, it is considered effective not only to pursue the Western environment but also to improve staff such as nurses and CRC. The number of Japanese patients necessary for Phase III studies is individual developmental strategy and needs to be examined by both companies and regulatory agencies.
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PMID:[Future directions of anticancer drug development in Japan]. 1828 81


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