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)

In men with metastatic hormone-refractory prostate cancer, androgen blockade produces dramatic and rapid declines in prostate-specific antigen (PSA), bone pain, and urinary tract obstruction. Nevertheless, there have been limited options with at best palliative results for patients who progress despite a castrate testosterone level. This paradigm changed in 2004 with the publication of 2 randomized clinical trials that demonstrated a 20% to 24% survival benefit for docetaxel-based therapy when compared to mitoxantrone and prednisone, data that supported US Food and Drug Administration approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer. This article reviews the preliminary data and the timing and sequencing implications of ongoing clinical trials. Studies are evaluating the combination of docetaxel with agents that target bone, tumor vasculature, and the vitamin D receptor as well as second-line agents, such as satraplatin. The role of immune therapy is also evolving, and further studies will define the optimal timing of chemotherapy with immune therapy.
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PMID:New paradigms for advanced prostate cancer. 1755 3

The proinflammatory chemokine interleukin-8 (IL-8) is undetectable in androgen-responsive prostate cancer cells (e.g., LNCaP and LAPC-4), but it is highly expressed in androgen-independent metastatic cells, such as PC-3. In this report, we show IL-8 functions in androgen independence, chemoresistance, tumor growth, and angiogenesis. We stably transfected LNCaP and LAPC-4 cells with IL-8 cDNA and selected IL-8-secreting (IL8-S) transfectants. The IL8-S transfectants that secreted IL-8 at levels similar to that secreted by PC-3 cells (100-170 ng/10(6) cells) were characterized. Continuous or transient exposure of LNCaP and LAPC-4 cells to IL-8 reduced their dependence on androgen for growth and decreased sensitivity (>3.5x) to an antiandrogen. IL-8-induced cell proliferation was mediated through CXCR1 and was independent of androgen receptor (AR). Quantitative PCR, immunoblotting, and transfection studies showed that IL8-S cells or IL-8-treated LAPC-4 cells exhibit a 2- to 3-fold reduction in PSA and AR levels, when compared with vector transfectants. IL8-S cells expressed 2- to 3-fold higher levels of phospho-EGFR, src, Akt, and nuclear factor kappaB (NF-kappaB) and showed increased survival when treated with docetaxel. This increase was blocked by NF-kappaB and src inhibitors, but not by an Akt inhibitor. IL8-S transfectants displayed a 3- to 5-fold increased motility, invasion, matrix metalloproteinase-9 and vascular endothelial growth factor production. LNCaP IL8-S cells grew rapidly as tumors, with increased microvessel density and abnormal tumor vasculature when compared with the tumors derived from their vector-transfected counterparts. Therefore, IL-8 is a molecular determinant of androgen-independent prostate cancer growth and progression.
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PMID:Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. 1763 96

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy.
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PMID:Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. 1805 50

Nanoparticles (size in nanometer range) provide a new mode of cancer drug delivery functioning as a carrier for entry through fenestrations in tumor vasculature allowing direct cell access. These particles allow exquisite modification for binding to cancer cell membranes, the microenvironment, or to cytoplasmic or nuclear receptor sites. This results in delivery of high drug concentrations to the targeted cancer cell, with reduced toxicity of normal tissue. Several such engineered drugs are in clinical practice, including liposomal doxorubicin and albumin conjugate paclitaxel. The carrier mediated paclitaxel has already shown significant efficacy in taxane resistant cancers, an approach highly relevant in prostate cancer, where taxanes are the treatment of choice. Other modifications including transferrin receptor and folate receptor targeted drug delivery molecules are in study. This new technology provides many exciting therapeutic approaches for targeted high concentration drug delivery to cancer cells with reduced injury of normal cells.
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PMID:Nanoparticles for drug delivery in cancer treatment. 1819 Aug 33

Interferon (IFN)-alpha is a cytokine with marked therapeutic activity in transplantable tumor models, that is in part due to angiogenesis inhibition. Aim of this study was to investigate the effects of IFN-alpha during the early phases of tumor development in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. To provide sustained IFN-alpha production, TRAMP mice were injected intraperitoneally with lentiviral vectors. IFN-alpha administration resulted in rapid and protracted upregulation of IFN-alpha-regulated genes associated with antiangiogenic and antiproliferative functions in the prostate of TRAMP mice, including guanylate-binding protein 1 (GBP-1), IFI204 and CXCL10-11. These transcriptional changes were accompanied by effects on the tumor vasculature, including significant reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, without induction of tumor necrosis. Intriguingly, GBP-1 and myxovirus resistance A, two IFN-regulated proteins, were found expressed in approximately 40% of human prostate cancer samples analyzed, suggesting expression of endogenous IFN-alpha. Overall, these findings demonstrate that IFN-alpha is able to counteract the angiogenic switch and impairs tumor cell proliferation in preinvasive lesions. Since the angiogenic switch also marks progression of human prostatic cancer, these results highlight the potential of angiogenesis inhibitors for the development of chemoprevention strategies in high-risk individuals.
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PMID:Interferon-alpha counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer. 1923 8

By frequent and protracted administration of conventional cytotoxic drugs without prolonged interruptions, the primary treatment target shifts from the tumor cell population to the tumor vasculature. This "metronomic" way of chemotherapy administration results in antivascular effects, the mechanistic basis of which remains to be fully elucidated. We outline the basic aspects of the metronomic concept, describe the results of clinical applications of such chemotherapy by focusing on studies in metastatic prostate cancer, and discuss certain shortcomings. Based on preclinical findings, we finally point to the possible ways to address these shortcomings in order to bring this novel and promising use of conventional anticancer agents to full fruition.
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PMID:Metronomic chemotherapy: principles and lessons learned from applications in the treatment of metastatic prostate cancer. 2003 83

A common model used for preclinical research was in vitro human tumor cell culture. An alternative model was the direct implantation of a unique patient's tumor biopsy specimens into immunodeficient host mice. Published data from PubMed (http://www.ncbi.nlm.nih.gov) and Current Contents Connect databases (http://thomsonreuters.com/products_services/science/science_products/a-z/current_contents_connect) were reviewed. Prostate cancer (PCa) heterotransplantation was evaluated using histopathology, morphology, cell differentiation, DNA content, tumor marker expression, metastases, tumor kinetics, tumor take rate and tumor vasculature in the first tumor heterotransplant. The heterotransplanted tumor retained the biological properties of the original tumor, such as morphology, degree of differentiation, pathology, secretory activity, expression of tumor markers and human vasculature. Human PCa heterotransplants have considerable experimental advantages over cell culture following xenotransplantation.
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PMID:Human prostate cancer heterotransplants: a review on this experimental model. 2036 54

The formation of a new vascular network by angiogenesis is a key driver in tumor growth and metastasis, making this an attractive therapeutic target. Different strategies are being developed to either prevent tumor angiogenesis or disrupt the tumor vasculature already in place. In this in vitro study, we investigated the antivascular properties of ENMD-1198, a new anticancer drug currently in clinical trials. ENMD-1198 is a new analogue of 2-methoxyestradiol, a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma and hormone-refractory prostate cancer. Using both bone marrow-derived and dermal microvascular endothelial cell lines, we analyzed the effect of ENMD-1198 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-methoxyestradiol at inhibiting endothelial cell proliferation, motility, migration, and morphogenesis. In addition, ENMD-1198 induced a significant decrease in vascular endothelial growth factor receptor-2 protein expression in endothelial cells. Furthermore, videomicroscopy experiments showed that ENMD-1198 was able to completely disrupt preformed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerization of the microtubule network and accumulation of actin stress fibers and large focal adhesions in vascular endothelial cells. Collectively, our results show that this new compound displays potent antivascular properties, and this study provides important insights into the mechanism of action of this promising new anticancer drug.
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PMID:ENMD-1198, a new analogue of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties. 2044 4

Treatment options for patients with advanced prostate cancer (PCa) remain limited. Improved understanding of the underlying molecular drivers of PCa pathogenesis, progression and resistance development has provided the fundamental basis for rational targeted drug design. Key findings in recent years include the identification of ETS gene rearrangements, the dissection of PCa molecular heterogeneity and the discovery that castration-resistant prostate cancer (CRPC) remains androgen driven despite the androgen-depleted milieu, thus making androgen receptor (AR) signaling a continued focus of molecularly targeted treatments. AR ligand-independent activation of tyrosine kinase prosurvival signaling cascades and angiogenesis have also been implicated in disease progression. A multitude of new molecularly targeted agents that abrogate AR signaling, inhibit the mitogenic and prosurvival signal transduction pathways, perturb the tumor-bone microenvironment, impair tumor vasculature, facilitate immune modulation and induce apoptosis are in clinical development and are highly likely to change the current treatment paradigm. It is clear that the success of these molecular targeted therapies hinges in part on optimal patient selection based on the molecular disease profile and an improved understanding of the mechanistic basis of acquired resistance. This review outlines the current clinical development of molecular targeted treatments in CRPC, with particular emphasis on agents that are in the later stages of clinical development, and details the challenges and future direction of developing these antitumor agents.
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PMID:Horizon scanning for novel therapeutics for the treatment of prostate cancer. 2094 42

Nestin is a class VI intermediate filament protein that was originally described as a neuronal stem cell marker during central nervous system (CNS) development, and is currently widely used in that capacity. Nestin is also expressed in non-neuronal immature or progenitor cells in normal tissues. Under pathological conditions, nestin is expressed in repair processes in the CNS, muscle, liver, and infarcted myocardium. Furthermore, increased nestin expression has been reported in various tumor cells, including CNS tumors, gastrointestinal stromal tumors, pancreatic cancer, prostate cancer, breast cancer, malignant melanoma, dermatofibrosarcoma protuberances, and thyroid tumors. Nestin is reported to correlate with aggressive growth, metastasis, and poor prognosis in some tumors; however, the roles of nestin in cancer cells have not been well characterized. Furthermore, nestin is more specifically expressed in proliferating small-sized tumor vessels in glioblastoma and gastric, colorectal, and prostate cancers than are other tumor vessel markers. These findings indicate that nestin may be a marker for newly synthesized tumor vessels and a therapeutic target for tumor angiogenesis. It has received a lot of attention recently as a cancer stem cell marker in various cancer cells including brain tumors, malignant rhabdoid tumors, and uterine, cervical, prostate, bladder, head and neck, ovarian, testicular, and pancreatic cancers. The purpose of this review is to clarify the roles of nestin in cancer cells and in tumor angiogenesis, and to examine the association between nestin and cancer stem cells. Nestin has the potential to serve as a molecular target for cancers with nestin-positive cancer cells and nestin-positive tumor vasculature.
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PMID:Nestin in gastrointestinal and other cancers: effects on cells and tumor angiogenesis. 2127 70


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