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Find video protocols related to scientific articles indexed in Pubmed.
Variant prostate carcinoma and elevated serum CA-125.
Can J Urol
PUBLISHED: 10-28-2014
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About 10% of tumors derived from nongynecologic, noncoelomic tissues react with the OC125 antibody. Some patients with advanced prostate cancer were found to have elevated serum CA-125 level.
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Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study.
J. Clin. Oncol.
PUBLISHED: 10-13-2014
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Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression.
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The Prostate Cancer Susceptibility Variant rs2735839 Near KLK3 Gene Is Associated with Aggressive Prostate Cancer and Can Stratify Gleason Score 7 Patients.
Clin. Cancer Res.
PUBLISHED: 10-03-2014
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Gleason score (GS) 7 prostate cancer is a heterogeneous disease with different clinical behavior. We sought to identify genetic biomarkers that may predict the aggressiveness of GS 7 diseases.
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Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.
Sci Transl Med
PUBLISHED: 09-05-2014
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Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors.
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Randomized phase 2 study of bone-targeted therapy containing strontium-89 in advanced castrate-sensitive prostate cancer.
Cancer
PUBLISHED: 08-22-2014
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Radiopharmaceutical use may improve the survival time of patients with castrate-resistant prostate cancer and bone metastases. Whether androgen-deprivation therapy (ADT) combined with bone-targeted therapy provides a clinical benefit to patients with advanced castrate-sensitive prostate cancer has not been investigated.
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Impact of a clinical trial initiative on clinical trial enrollment in a multidisciplinary prostate cancer clinic.
J Natl Compr Canc Netw
PUBLISHED: 07-05-2014
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Clinical oncology trials are hampered by low accrual rates, with fewer than 5% of adult patients with cancer treated on study. Clinical trial enrollment was evaluated at The University of Texas MD Anderson Cancer Center's Multidisciplinary Prostate Cancer Clinic (MPCC) to assess whether a clinical trial initiative, introduced in 2006, impacted enrollment. The trial initiative included posting trial-specific information in clinic, educating patients about appropriate clinical trial options during the treatment recommendation discussion, and providing patients with trial-specific educational information. The investigators evaluated the frequency of clinical trial enrollment for men with newly diagnosed prostate cancer seen in the MPCC from 2004 to 2008. Logistic regression evaluated the impact of patient characteristics and the clinical trial initiative on trial enrollment. The median age of the 1370 men was 64 years; 32% had low-risk, 49% had intermediate-risk, and 19% had high-risk disease. Overall, 74% enrolled in at least one trial and 29% enrolled in more than one trial. Trial enrollment increased from 39% before the initiative (127/326) to 84% (880/1044) after the trial initiative. Patient enrollment increased in laboratory studies (from 25% to 80%), quality-of-life studies (from 10% to 26%), and studies evaluating investigational treatments and systemic agents (from 6% to 15%) after the trial initiative. In multivariate analysis, younger men (P<.001) and men seen after implementation of the clinical trial initiative (P<.001) were more likely to enroll in trials. Clinical trial enrollment in the MPCC was substantially higher than that seen nationally in adult patients with cancer, and enrollment rates increased after the introduction of a clinical trial initiative.
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Aggressive variants of castration-resistant prostate cancer.
Clin. Cancer Res.
PUBLISHED: 04-11-2014
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A subset of patients with advanced castration-resistant prostate cancer may eventually evolve into an androgen receptor (AR)-independent phenotype, with a clinical picture associated with the development of rapidly progressive disease involving visceral sites and hormone refractoriness, often in the setting of a low or modestly rising serum prostate-specific antigen level. Biopsies performed in such patients may vary, ranging from poorly differentiated carcinomas to mixed adenocarcinoma-small cell carcinomas to pure small cell carcinomas. These aggressive tumors often demonstrate low or absent AR protein expression and, in some cases, express markers of neuroendocrine differentiation. Because tumor morphology is not always predicted by clinical behavior, the terms "anaplastic prostate cancer" or "neuroendocrine prostate cancer" have been used descriptively to describe these rapidly growing clinical features. Patients meeting clinical criteria of anaplastic prostate cancer have been shown to predict for poor prognosis, and these patients may be considered for platinum-based chemotherapy treatment regimens. Therefore, understanding variants within the spectrum of advanced prostate cancer has important diagnostic and treatment implications.
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Genes with a large intronic burden show greater evolutionary conservation on the protein level.
BMC Evol. Biol.
PUBLISHED: 03-11-2014
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The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene.
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How to get the most from microarray data: advice from reverse genomics.
BMC Genomics
PUBLISHED: 03-10-2014
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Whole-genome profiling of gene expression is a powerful tool for identifying cancer-associated genes. Genes differentially expressed between normal and tumorous tissues are usually considered to be cancer associated. We recently demonstrated that the analysis of interindividual variation in gene expression can be useful for identifying cancer associated genes. The goal of this study was to identify the best microarray data-derived predictor of known cancer associated genes.
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Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302).
Eur. Urol.
PUBLISHED: 02-24-2014
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Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.
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PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer.
Cancer Res.
PUBLISHED: 01-28-2014
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Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.
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Molecular Characterization of Enzalutamide-treated Bone Metastatic Castration-resistant Prostate Cancer.
Eur. Urol.
PUBLISHED: 01-10-2014
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Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).
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Posttranslational regulation of Akt in human cancer.
Cell Biosci
PUBLISHED: 01-01-2014
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Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy.
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Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial.
Lancet Oncol.
PUBLISHED: 11-08-2013
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Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.
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Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial.
Lancet Oncol.
PUBLISHED: 09-25-2013
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Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial.
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Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy.
Eur. J. Cancer
PUBLISHED: 07-16-2013
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In a recent randomised, double-blind, phase III clinical trial among 1195 patients with metastatic castration-resistant prostate cancer (mCRPC) who had failed docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong overall survival compared with prednisone alone. Here we report on the impact of abiraterone therapy on the health-related quality of life (HRQoL) observed during this trial, assessed using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.
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Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer.
Cancer Discov
PUBLISHED: 06-28-2013
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Recently, many therapeutic agents for prostate cancer have been approved that target the androgen receptor and/or the prostate tumor microenvironment. Each of these therapies has modestly increased patient survival. A better understanding of when in the course of prostate cancer progression specific therapies should be applied, and of what biomarkers would indicate when resistance arises, would almost certainly improve survival due to these therapies. Thus, applying the armamentarium of therapeutic agents in the right sequences in the right combination at the right time is a major goal in prostate cancer treatment. For this to occur, an understanding of prostate cancer evolution during progression is required. In this review, we discuss the current understanding of prostate cancer progression, but challenge the prevailing view by proposing a new model of prostate cancer progression, with the goal of improving biologic classification and treatment strategies. We use this model to discuss how integrating clinical and basic understanding of prostate cancer will lead to better implementation of molecularly targeted therapeutics and improve patient survival.
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Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure.
J Oncol Pract
PUBLISHED: 06-25-2013
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Contemporary tumor-directed therapies for metastatic castration-resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure.
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Modified logistic regression models using gene coexpression and clinical features to predict prostate cancer progression.
Comput Math Methods Med
PUBLISHED: 06-12-2013
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Predicting disease progression is one of the most challenging problems in prostate cancer research. Adding gene expression data to prediction models that are based on clinical features has been proposed to improve accuracy. In the current study, we applied a logistic regression (LR) model combining clinical features and gene co-expression data to improve the accuracy of the prediction of prostate cancer progression. The top-scoring pair (TSP) method was used to select genes for the model. The proposed models not only preserved the basic properties of the TSP algorithm but also incorporated the clinical features into the prognostic models. Based on the statistical inference with the iterative cross validation, we demonstrated that prediction LR models that included genes selected by the TSP method provided better predictions of prostate cancer progression than those using clinical variables only and/or those that included genes selected by the one-gene-at-a-time approach. Thus, we conclude that TSP selection is a useful tool for feature (and/or gene) selection to use in prognostic models and our model also provides an alternative for predicting prostate cancer progression.
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Platinum-based chemotherapy for variant castrate-resistant prostate cancer.
Clin. Cancer Res.
PUBLISHED: 05-06-2013
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Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy.
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Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression.
Cell
PUBLISHED: 03-20-2013
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Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.
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Ligand-independent activation of MET through IGF-1/IGF-1R signaling.
Int. J. Cancer
PUBLISHED: 03-06-2013
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The receptor tyrosine kinase, MET, has been implicated in tumorigenesis and metastasis of many solid tumors, by multiple mechanisms, including cross talk with epidermal growth factor receptor. In this study, we examined the role of insulin-like growth factor receptor-1 (IGF-1R) signaling in MET activation, focusing on prostate cancer cells. Stimulation of the prostate cancer cell line PC3 with IGF-1 induces a delayed phosphorylation of MET at multiple sites (indicative of full activation), reaching a maximum 18 hr after IGF-1 addition. MET activation does not require the sole MET ligand hepatocyte growth factor (HGF), but does require transcription to occur. Furthermore, direct injection of IGF-1 is sufficient to induce MET activation in vivo, in a PC3 xenograft model. Pharmacologic or genetic inhibition of the tyrosine kinase, Src, abolishes MET phosphorylation, and expression of activated Src is sufficient to induce Met phosphorylation in the absence of IGF-1 stimulation. Activated MET is essential for IGF-1-mediated increased migration of PC3 cells, demonstrating an important biologic effect of IGF-1-mediated MET activation. Finally, we demonstrate that IGF-1-induced delayed MET activation occurs in multiple cell lines which express both the receptors, suggesting that IGF-1R-mediated MET activation may contribute to tumorigenic properties of multiple cancer types when both growth factor receptors are expressed. The results further suggest that MET may be activated by multiple receptor tyrosine kinase receptors, and dual targeting of these receptors may be important therapeutically.
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Targeting constitutively activated ?1 integrins inhibits prostate cancer metastasis.
Mol. Cancer Res.
PUBLISHED: 01-21-2013
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Disseminated prostate cancer cells must survive in circulation for metastasis to occur. Mechanisms by which these cells survive are not well understood. By immunohistochemistry of human tissues, we found that levels of ?1 integrins and integrin-induced autophosphorylation of FAK (pFAK-Y397) are increased in prostate cancer cells in primary prostate cancer and lymph node metastases, suggesting that ?1 integrin activation occurs in metastatic progression of prostate cancer. A conformation-sensitive antibody, 9EG7, was used to examine ?1 integrin activation. We found that ?1 integrins are constitutively activated in highly metastatic PC3 and PC3-mm2 cells, with less activation in low metastatic LNCaP and C4-2B4 cells. Increased ?1 integrin activation as well as the anoikis resistance in prostate cancer cells correlated with metastatic potential in vivo. Knockdown of ?1 integrin abrogated anoikis resistance in PC3-mm2 cells. In agreement with ?1 integrin activation, PC3-mm2 cells strongly adhered to type I collagen and fibronectin, a process inhibited by the ?1 integrin-neutralizing antibody mAb 33B6. mAb 33B6 also inhibited the phosphorylation of ?1 integrin downstream effectors, focal adhesion kinase (FAK) and AKT, leading to a 3-fold increase in PC3-mm2 apoptosis. Systemic delivery of mAb 33B6 suppressed spontaneous metastasis of PC3-mm2 from the prostate to distant lymph nodes following intraprostatic injection and suppressed metastasis of PC3-mm2 to multiple organs following intracardiac injection. Thus, constitutively activated ?1 integrins play a role in survival of PC3-mm2 cells in circulation and represent a potential target for metastasis prevention.
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Increased serum insulin-like growth factor-1 levels are associated with prolonged response to dasatinib-based regimens in metastatic prostate cancer.
Prostate
PUBLISHED: 01-08-2013
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Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers in a phase I/II clinical trial in metastatic CRPC. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions.
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Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone.
J. Clin. Oncol.
PUBLISHED: 12-19-2011
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Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.
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Modeling a lethal prostate cancer variant with small-cell carcinoma features.
Clin. Cancer Res.
PUBLISHED: 12-12-2011
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Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology.
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Personalized oncology through integrative high-throughput sequencing: a pilot study.
Sci Transl Med
PUBLISHED: 12-03-2011
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Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.
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Vascular ligand-receptor mapping by direct combinatorial selection in cancer patients.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-02-2011
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Molecules differentially expressed in blood vessels among organs or between damaged and normal tissues, are attractive therapy targets; however, their identification within the human vasculature is challenging. Here we screened a peptide library in cancer patients to uncover ligand-receptors common or specific to certain vascular beds. Surveying ~2.35 x 10(6) motifs recovered from biopsies yielded a nonrandom distribution, indicating that systemic tissue targeting is feasible. High-throughput analysis by similarity search, protein arrays, and affinity chromatography revealed four native ligand-receptors, three of which were previously unrecognized. Two are shared among multiple tissues (integrin ?4/annexin A4 and cathepsin B/apolipoprotein E3) and the other two have a restricted and specific distribution in normal tissue (prohibitin/annexin A2 in white adipose tissue) or cancer (RAGE/leukocyte proteinase-3 in bone metastases). These findings provide vascular molecular markers for biotechnology and medical applications.
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The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials.
Expert Opin Investig Drugs
PUBLISHED: 10-28-2011
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An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer.
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Novel therapies for metastatic castrate-resistant prostate cancer.
J. Natl. Cancer Inst.
PUBLISHED: 09-13-2011
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Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.
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Understanding the lethal variant of prostate cancer: power of examining extremes.
Cancer Discov
PUBLISHED: 09-02-2011
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Small cell prostate carcinoma is a lethal variant of castration-resistant prostate cancer. Beltran and colleagues identified overexpression and amplification of both aurora kinase A (AURKA) and the MYCN proto-oncogene in the small cell prostate carcinomas and propose Aurora kinase A as a potential therapeutic target in this disease subset.
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Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling.
Histopathology
PUBLISHED: 06-29-2011
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The hedgehog (Hh) signalling pathway has been implicated in the pathogenesis and aggressiveness of prostate cancer through epithelial-mesenchymal interactions. The aim of this study was to elucidate the cell-type partitioned expression of the Hh pathway biomarkers in the non-neoplastic and tumour microenvironments and to correlate it with the grade and stage of prostate cancer.
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Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response.
Clin. Cancer Res.
PUBLISHED: 06-01-2011
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Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response.
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Abiraterone and increased survival in metastatic prostate cancer.
N. Engl. J. Med.
PUBLISHED: 05-27-2011
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Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
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Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment.
J. Clin. Oncol.
PUBLISHED: 05-23-2011
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Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment.
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Androgen regulation of 5?-reductase isoenzymes in prostate cancer: implications for prostate cancer prevention.
PLoS ONE
PUBLISHED: 05-16-2011
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The enzyme 5?-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5?-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5?-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5?-reductase isoenzymes in a cell type-specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5?-reductase isoenzymes may confer response or resistance to 5?-reductase inhibitors and thus may have importance in prostate cancer prevention.
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Aberrant expression of katanin p60 in prostate cancer bone metastasis.
Prostate
PUBLISHED: 05-09-2011
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Katanin p60 is a microtubule-severing protein and is involved in microtubule cytoskeleton organization in both mitotic and non-mitotic processes. Its role in cancer metastasis is unknown.
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Current and emerging treatment modalities for metastatic castration-resistant prostate cancer.
BJU Int.
PUBLISHED: 03-09-2011
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Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.
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Maximizing outcomes in genitourinary cancers across the treatment continuum.
BJU Int.
PUBLISHED: 03-09-2011
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Key controversies concerning the management of genitourinary cancers across the treatment continua were discussed at the second annual Interactive Genitourinary Cancer Conference (IGUCC) held in February 2010 in Athens, Greece. Prostate cancer is the most common form of cancer among western men and prevention strategies are needed. Trials evaluating 5?-reductase inhibitors have reported beneficial and clinically meaningful results, but uptake remains low for primary prostate cancer prevention. Prostate cancer detection programmes are also important as curative treatments for advanced disease are unavailable. Two large landmark randomized controlled trials reported conflicting results concerning screening efficacy and uncovered high levels of over-diagnosis and potential over-treatment. Tailored management strategies after diagnosis are important and predictive markers that distinguish between aggressive and indolent tumours are needed. The majority of newly diagnosed cases of prostate cancer are clinically localized. Active surveillance of favourable risk patients may be beneficial in the intermediate term, while an integrated approach of multi-modality therapy in patients with adverse features is recommended. The benefits of new technologies such as high-intensity focused ultrasound (HIFU) and robotic prostatectomy have not been established in prospective randomized trials vs current standards of care. A multidisciplinary approach is essential to evolving the management of advanced prostate cancer into a chronic disease paradigm. Docetaxel plus prednisone is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC), but the optimal timing of chemotherapy initiation has not been addressed in randomized clinical trials. Retrospective analyses suggest that asymptomatic patients with adverse prognostic factors for survival may also benefit from receiving chemotherapy. Bladder cancer is a common malignancy and the most expensive cancer per patient. Non-muscle-invasive bladder cancer is a heterogenous disease that requires dynamic multidisciplinary management. Aggressive early intervention may be beneficial in some cases. Platinum-based therapies represent the first-line standard of care for advanced bladder cancer, but the maximum benefit may have been reached for conventional chemotherapies and new strategies are needed. Several ongoing clinical trials are assessing combination chemotherapy and targeted therapy.
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Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.
Cancer
PUBLISHED: 01-06-2011
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To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.
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Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patients tumor: morphological, immunohistochemical, and gene expression profiles.
Prostate
PUBLISHED: 07-20-2010
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Small-cell carcinoma (SCC) of the prostate is an AR-negative variant of prostate cancer found at progression in 10-20% of castrate-resistant disease. Its finding predicts a distinct clinical course and a poor prognosis. Large-cell neuroendocrine carcinoma (LCNEC) is a much rarer variant that behaves similarly to SCC. The biological mechanisms that drive these disease variants are poorly understood.
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Adipose tissue-derived stem cells promote prostate tumor growth.
Prostate
PUBLISHED: 06-22-2010
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Recent evidence indicates that cancer stem cells play an important role in tumor initiation and maintenance. Additionally, the effect of tissue-resident stem cells located in the surrounding healthy tissue on tumor progression has been demonstrated. While most knowledge has been derived from studies of breast cancer cells, little is known regarding the influence of tissue resident stem cells on the tumor biology of prostate cancer.
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Multimodality therapy: bone-targeted radioisotope therapy of prostate cancer.
Clin Adv Hematol Oncol
PUBLISHED: 06-17-2010
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Accumulating data suggest that bone-seeking radiopharmaceuticals can be used to treat prostate cancer bone metastasis and improve the clinical outcome of patients with advanced prostate cancer. It remains to be elucidated whether radiopharmaceuticals enhance the disruption of the onco-niche or the eradication of micrometastatic cells in the bone marrow. The purpose of this review is to investigate the role of bone-targeted radioisotope therapy in the setting of multimodality therapy for advanced prostate cancer. We examine available data and evaluate whether dose escalation, newer generations, or repeated dosing of radiopharmaceuticals enhance their antitumor effects and whether their combination with hormone ablative therapy, chemotherapy, or novel targeted therapy can improve clinical efficacy.
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Cadherin-11 increases migration and invasion of prostate cancer cells and enhances their interaction with osteoblasts.
Cancer Res.
PUBLISHED: 05-18-2010
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Cell adhesion molecules have been implicated in the colonization of cancer cells to distant organs. Prostate cancer (PCa) has a propensity to metastasize to bone, and cadherin-11, which is an osteoblast cadherin aberrantly expressed in PCa cells derived from bone metastases, has been shown to play a role in the metastasis of PCa cells to bone. However, the mechanism by which cadherin-11 is involved in this process is not known. Here, we show that expression of cadherin-11 in cadherin-11-negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer and also stimulates C4-2B4 cell migration and invasiveness. The downregulation of cadherin-11 in cadherin-11-expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane (JMD) and beta-catenin binding domains (CBS) in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion, but not spreading. Gene array analyses showed that several invasion-related genes, including MMP-7 and MMP-15, are upregulated in cadherin-11-expressing, but not in cad11-DeltaJMD-expressing or cad11-DeltaCBS-expressing, C4-2B4 cells. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness that may facilitate the metastatic colonization of PCa cells in bone.
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Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
Clin. Cancer Res.
PUBLISHED: 05-11-2010
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Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.
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Prioritizing genes associated with prostate cancer development.
BMC Cancer
PUBLISHED: 03-25-2010
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The genetic control of prostate cancer development is poorly understood. Large numbers of gene-expression datasets on different aspects of prostate tumorigenesis are available. We used these data to identify and prioritize candidate genes associated with the development of prostate cancer and bone metastases. Our working hypothesis was that combining meta-analyses on different but overlapping steps of prostate tumorigenesis will improve identification of genes associated with prostate cancer development.
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A new therapy paradigm for prostate cancer founded on clinical observations.
Clin. Cancer Res.
PUBLISHED: 02-09-2010
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Efficacy equivalent to that reported in other common adult solid tumors considered to be chemotherapy-sensitive has been reported with Docetaxel in patients with castrate-resistant prostate cancer. However, in contrast to other cancers, the expected increase in efficacy with the use of chemotherapy in earlier disease states has not been reported to date in prostate cancer. On the basis of these observations, we speculated that the therapy development paradigm used successfully in other cancers may not apply to the majority of prostate cancers. Several lines of supporting clinical and experimental observations implicate the tumor microenvironment in prostate carcinogenesis and resistance to therapy. We conclude that a foundation to guide the development of therapy for prostate cancer is required. The therapy paradigm we propose accounts for the central role of the tumor microenvironment in bone and, if correct, will lead to microenvironment-targeted therapy.
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Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors.
Cancer Treat. Rev.
PUBLISHED: 02-02-2010
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SRC is a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes. It has therefore been prioritized as a candidate therapeutic target in patients with solid tumors. Several SRC inhibitors are now in development, of which dasatinib has been most explored. Preclinical studies in a wide variety of solid tumor cell lines, including prostate, breast and glioma, have shown that that dasatinib acts as a cytostatic agent, inhibiting the processes of cell proliferation, invasion and metastasis. Dasatinib also inhibits the activity of osteoclasts, which have a major role in the development of metastatic bone lesions. Dasatinib has additive or synergistic activity in combination with a number of other agents, including cytotoxic agents and targeted therapies, providing a rationale for combination treatment in a clinical setting. Emerging clinical data with dasatinib support experimental observations, with preliminary phase 1 and 2 data demonstrating activity, both as a single agent and as combination therapy, in a range of solid tumors. Future clinical trials will further assess the clinical value of SRC inhibition with dasatinib.
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Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.
Cancer Biol. Ther.
PUBLISHED: 11-08-2009
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Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation.
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Candidate pathways and genes for prostate cancer: a meta-analysis of gene expression data.
BMC Med Genomics
PUBLISHED: 08-04-2009
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The genetic mechanisms of prostate tumorigenesis remain poorly understood, but with the advent of gene expression array capabilities, we can now produce a large amount of data that can be used to explore the molecular and genetic mechanisms of prostate tumorigenesis.
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Morphologic characterization of preoperatively treated prostate cancer: toward a post-therapy histologic classification.
Eur. Urol.
PUBLISHED: 07-12-2009
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Preoperative treatment of prostate cancer (PCa) changes morphology of residual tumors so that the Gleason score is no longer valid.
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Housekeeping genes in prostate tumorigenesis.
Int. J. Cancer
PUBLISHED: 06-25-2009
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Housekeeping (HK) genes are involved in basic cellular functions and tend to be constitutively expressed across various tissues and conditions. A number of studies have analyzed the value of HK genes as an internal standard for assessing gene expression, but the role of HK genes in cancer development has never been specifically addressed. In this study, we sought to evaluate the expression of HK genes during prostate tumorigenesis. We performed a meta-analysis of gene expression during the transition from normal prostate (NP) to localized prostate cancer (LPC) (i.e., NP > LPC) and from localized to metastatic prostate cancer (MPC) (i.e., LPC > MPC). We found that HK genes are more likely to be differentially expressed during prostate tumorigenesis than is the average gene in the human genome, suggesting that prostate tumorigenesis is driven by modulation of the expression of HK genes. Cell-cycle genes and proliferation markers were up-regulated in both NP > LPC and LPC > MPC transitions. We also found that the genes encoding ribosomal proteins were up-regulated in the NP > LPC and down-regulated in the LPC > MPC transition. The expression of heat shock proteins was up-regulated during the LPC > MPC transition, suggesting that in its advanced stages, prostate tumor is under cellular stress. The results of these analyses suggest that during prostate tumorigenesis, there is a period when the tumor is under cellular stress and, therefore, may be the most vulnerable and responsive to treatment.
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GWAS meets microarray: are the results of genome-wide association studies and gene-expression profiling consistent? Prostate cancer as an example.
PLoS ONE
PUBLISHED: 05-11-2009
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Genome-wide association studies (GWASs) and global profiling of gene expression (microarrays) are two major technological breakthroughs that allow hypothesis-free identification of candidate genes associated with tumorigenesis. It is not obvious whether there is a consistency between the candidate genes identified by GWAS (GWAS genes) and those identified by profiling gene expression (microarray genes).
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Prostate cancer: thalidomide for prostate cancer: is there progress?
Nat Rev Urol
PUBLISHED: 05-09-2009
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Upon its reinvention, thalidomide was quickly applied to microenvironment-dependent diseases such as multiple myeloma, yet its role in the solid tumor spectrum has not been validated. A report into recurrent prostate cancer by Figg et al. shows that thalidomide can reduce time to PSA progression in patients treated with androgen deprivation therapy.
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Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer.
J. Clin. Oncol.
PUBLISHED: 05-04-2009
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Samarium-153 ((153)Sm) lexidronam is a bone-targeting radiopharmaceutical with a short physical half-life and a favorable toxicity profile. We evaluated the safety and feasibility of a concurrent combination of weekly docetaxel with repeated (153)Sm-lexidronam in patients with castration-resistant prostate cancer (CRPC).
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Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma.
BJU Int.
PUBLISHED: 03-31-2009
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To prospectively establish objective selection criteria for metastasectomy in patients with metastatic renal cell carcinoma (mRCC).
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NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells.
Clin. Cancer Res.
PUBLISHED: 03-10-2009
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Different vaccination strategies against the NY-ESO-1 antigen have been employed in an attempt to induce antitumor immune responses. Antigen-specific effector T-cell responses have been reported in a subset of vaccinated patients; however, these responses have not consistently correlated with disease regression. Here, we report for the first time clinical and immune responses generated by the NY-ESO-1 DNA vaccine administered by particle-mediated epidermal delivery to cancer patients.
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Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer.
J. Natl. Cancer Inst.
PUBLISHED: 02-24-2009
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Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.
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Department of Defense prostate cancer clinical trials consortium: a new instrument for prostate cancer clinical research.
Clin Genitourin Cancer
PUBLISHED: 02-14-2009
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In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC).
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Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity.
Cancer Biol. Ther.
PUBLISHED: 02-08-2009
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RNA-dependent protein kinase is an interferon-induced, double-stranded (ds), RNA-activated serine/threonine protein kinase involved in the eukaryotic response to viral infection. While PKR also functions in cellular differentiation, growth control and apoptosis, its role in human cancer remains poorly understood. To explore a role for PKR in human cancer, we evaluated PKR expression and function in a series of cancer cell lines from different tumor types. We observed that PKR protein expression is high in various cancer cells and low in normal cells. Knockdown of PKR protein expression by PKR siRNA induced cell death, indicating a PKR-dependent survival pathway under normal growth conditions. Inhibition of PKR signaling using a dominant negative adenoviral PKR mutant (Ad-Delta6PKR) also induced cancer cell apoptosis via a mechanism that blocks activation of AKT-mediated survival while simultaneously inducing ER stress. ER stress-mediated apoptosis was evidenced by unregulated expression of phosphorylated JNK (p-JNK), phosphorylated cJun (p-cJun), and caspase-4 and was significantly reduced in cancer cells treated with JNK and caspase-4 inhibitors. We further demonstrated that inhibition of PKR signaling via either siRNA or Ad-Delta6PKR sensitizes cancer cells to etoposide or cisplatin-mediated cell death. Our results suggest a rationale to develop therapeutic strategies that target PKR signaling in human cancer cells.
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Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 02-06-2009
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Cytotoxic lymphocyte antigen-4 (CTLA-4) blockade is an active immunotherapeutic strategy that is currently in clinical trials in cancer. There are several ongoing trials of anti-CTLA-4 in the metastatic setting of prostate cancer patients with reported clinical responses consisting of decreases in the prostate specific antigen (PSA) tumor marker for some patients. Immunologic markers that correlate with these clinical responses are necessary to guide further development of anti-CTLA-4 therapy in the treatment of cancer patients. We recently reported that CD4(+) inducible co-stimulator (ICOS)(hi) T cells that produce interferon-gamma (IFN-gamma) are increased in the peripheral blood and tumor tissues of bladder cancer patients treated with anti-CTLA-4 antibody. Here we present data from the same clinical trial in bladder cancer patients demonstrating a higher frequency of CD4(+)ICOS(hi) T cells and IFN-gamma mRNA levels in nonmalignant prostate tissues and incidental prostate tumor tissues removed at the time of radical cystoprostatectomy. Our data suggest immunologic markers that can be used to monitor prostate cancer patients who receive anti-CTLA-4 therapy and indicate that the immunologic impact of anti-CTLA-4 antibody can occur in both tumor and nonmalignant tissues. These data should be taken into consideration for evaluation of efficacy as well as immune-related adverse events associated with anti-CTLA-4 therapy.
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Targeting Src signaling in metastatic bone disease.
Int. J. Cancer
PUBLISHED: 01-08-2009
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Src is a tyrosine kinase involved in the regulation of a range of cellular processes including proliferation, adhesion, motility and survival. In addition, it is a key regulator of bone metabolism. Src has been implicated in the pathogenesis of a number of cancers, and has been found to be overexpressed in breast, prostate, colorectal, pancreatic and nonsmall-cell lung tumors. There is also evidence that aberrant Src signaling may contribute to the increased osteoclastic activity associated with bone metastases. Bone metastases frequently occur in cancer patients with advanced disease. The metastasized cells disrupt normal bone remodeling pathways resulting in the release of growth factors that further promote tumor growth. Thus, a cycle of metastatic bone destruction is initiated, leading to compromised skeletal integrity and substantially reduced quality of life. Because of the role of Src in both cancer development and in bone metabolism, it may provide a therapeutic target for patients with bone metastases.
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Combined Inhibition of IGF-1R/IR and Src family kinases enhances antitumor effects in prostate cancer by decreasing activated survival pathways.
PLoS ONE
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Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways.
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Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.
J. Clin. Oncol.
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Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.
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Building a statistical model for predicting cancer genes.
PLoS ONE
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More than 400 cancer genes have been identified in the human genome. The list is not yet complete. Statistical models predicting cancer genes may help with identification of novel cancer gene candidates. We used known prostate cancer (PCa) genes (identified through KnowledgeNet) as a training set to build a binary logistic regression model identifying PCa genes. Internal and external validation of the model was conducted using a validation set (also from KnowledgeNet), permutations, and external data on genes with recurrent prostate tumor mutations. We evaluated a set of 33 gene characteristics as predictors. Sixteen of the original 33 predictors were significant in the model. We found that a typical PCa gene is a prostate-specific transcription factor, kinase, or phosphatase with high interindividual variance of the expression level in adjacent normal prostate tissue and differential expression between normal prostate tissue and primary tumor. PCa genes are likely to have an antiapoptotic effect and to play a role in cell proliferation, angiogenesis, and cell adhesion. Their proteins are likely to be ubiquitinated or sumoylated but not acetylated. A number of novel PCa candidates have been proposed. Functional annotations of novel candidates identified antiapoptosis, regulation of cell proliferation, positive regulation of kinase activity, positive regulation of transferase activity, angiogenesis, positive regulation of cell division, and cell adhesion as top functions. We provide the list of the top 200 predicted PCa genes, which can be used as candidates for experimental validation. The model may be modified to predict genes for other cancer sites.
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Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised tri
Lancet Oncol.
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Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.