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Find video protocols related to scientific articles indexed in Pubmed.
Anti-tumor effect of novel cationic biomaterials in prostate cancer.
Anticancer Res.
PUBLISHED: 07-31-2014
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Tumor cells expressing excessive anionic-charged sialic acid can be potentially targeted by cationic polymers which may inhibit tumor growth. In the present study, three new families of cationic polymers were synthesized to assess their effects on prostate cancer cells.
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In vitro method to observe E-selectin-mediated interactions between prostate circulating tumor cells derived from patients and human endothelial cells.
J Vis Exp
PUBLISHED: 06-05-2014
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Metastasis is a process in which tumor cells shed from the primary tumor intravasate blood vascular and lymphatic system, thereby, gaining access to extravasate and form a secondary niche. The extravasation of tumor cells from the blood vascular system can be studied using endothelial cells (ECs) and tumor cells obtained from different cell lines. Initial studies were conducted using static conditions but it has been well documented that ECs behave differently under physiological flow conditions. Therefore, different flow chamber assemblies are currently being used to studying cancer cell interactions with ECs. Current flow chamber assemblies offer reproducible results using either different cell lines or fluid at different shear stress conditions. However, to observe and study interactions with rare cells such as circulating tumor cells (CTCs), certain changes are required to be made to the conventional flow chamber assembly. CTCs are a rare cell population among millions of blood cells. Consequently, it is difficult to obtain a pure population of CTCs. Contamination of CTCs with different types of cells normally found in the circulation is inevitable using present enrichment or depletion techniques. In the present report, we describe a unique method to fluorescently label circulating prostate cancer cells and study their interactions with ECs in a self-assembled flow chamber system. This technique can be further applied to observe interactions between prostate CTCs and any protein of interest.
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Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential.
Mol Diagn Ther
PUBLISHED: 05-10-2014
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Circulating tumor cells (CTCs) have emerged as a viable solution to the lack of tumor tissue availability for patients with a variety of solid tumors, including prostate cancer. Different approaches have been used to capture this tumor cell population and several of these techniques have been used to assess the potential role of CTCs as a biological marker to predict treatment efficacy and clinical outcome. CTCs are now considered a strong tool to understand the molecular characteristics of prostate cancer, and to be used and analyzed as a 'liquid biopsy' in the attempt to grasp the biological portrait of the disease in the individual patient.
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The role of HIF1? in renal cell carcinoma tumorigenesis.
J. Mol. Med.
PUBLISHED: 04-09-2014
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The transcription factor HIF1? is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1? was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2? in ccRCC, but a tumor suppressor role for HIF1?, leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1? and HIF2? in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1? in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1? and HIF2? is incomplete and that further research is required to determine the diverse roles of HIF1? and HIF2? in ccRCC.
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Immunologics and chemotherapeutics for renal cell carcinoma.
Semin Intervent Radiol
PUBLISHED: 03-06-2014
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Treatment of metastatic renal cell carcinoma remains a challenge for clinicians. Traditional chemotherapy is ineffective and immunotherapy with interleukin-2 is only occasionally beneficial. The development of numerous agents targeting vascular endothelial growth factor and mammalian target of rapamycin signaling pathways that have been studied in phase III trials have resulted in significant improvement in survival for patients with clear cell renal cell carcinoma. Currently available U.S. Food and Drug Administration-approved first line targeted agents include sunitinib, pazopanib, temsirolimus, and bevacizumab (with interferon), while axitinib, everolimus, and sorafenib are most extensively used following progression as second- or third line therapy. Attempts to augment the activity of these agents by combining them together or with chemotherapy or immunotherapy have not yet proven to improve outcomes. As a result, the sequential use of single agents remains the current standard of care.
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Androgen receptor splice variants determine taxane sensitivity in prostate cancer.
Cancer Res.
PUBLISHED: 02-20-2014
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Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active androgen receptor splice variants that drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC); however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for androgen receptor nuclear translocation and activity. In this study, we used a set of androgen receptor deletion mutants to identify the microtubule-binding domain of the androgen receptor, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant androgen receptor splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or coprecipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumor xenografts displayed docetaxel resistance. Our results suggest that androgen receptor variants that accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of taxanes, suggesting a mechanistic rationale to customize treatments for patients with CRPC, which might improve outcomes.
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Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma.
Cancer
PUBLISHED: 09-06-2013
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Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC.
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Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer.
Clin. Cancer Res.
PUBLISHED: 05-28-2013
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To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival.
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Activation of HIF2? in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis.
Cancer Res.
PUBLISHED: 02-27-2013
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Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1? (HIF1?) and HIF2? has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2? (P405A, P530A, and N851A, named as HIF2?M3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1?M3 oncogenesis when coexpressed with constitutively active HIF1?M3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), ?H2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2? is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2? activation is critical for ccRCC tumorigenesis.
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Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer.
Neoplasia
PUBLISHED: 01-30-2013
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Neuroendocrine prostate cancer (NEPC), also referred to as anaplastic prostate cancer, is a lethal tumor that most commonly arises in late stages of prostate adenocarcinoma (PCA) with predilection to metastasize to visceral organs. In the current study, we explore for evidence that Aurora kinase A (AURKA) and N-myc (MYCN) gene abnormalities are harbingers of treatment-related NEPC (t-NEPC). We studied primary prostate tissue from 15 hormone naïve PCAs, 51 castration-resistant prostate cancers, and 15 metastatic tumors from 72 patients at different stages of disease progression to t-NEPC, some with multiple specimens. Histologic evaluation, immunohistochemistry, and fluorescence in situ hybridization were performed and correlated with clinical variables. AURKA amplification was identified in overall 65% of PCAs (hormone naïve and treated) from patients that developed t-NEPC and in 86% of metastases. Concurrent amplification of MYCN was present in 70% of primary PCAs, 69% of treated PCAs, and 83% of metastases. In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in only 5% of 169 cases. When metastatic t-NEPC was compared to primary PCA from the same patients, there was 100% concordance of ERG rearrangement, 100% concordance of AURKA amplification, and 60% concordance of MYCN amplification. In tumors with mixed features, there was also 100% concordance of ERG rearrangement and 94% concordance of AURKA and MYCN co-amplification between areas of NEPC and adenocarcinoma. AURKA and MYCN amplifications may be prognostic and predictive biomarkers, as they are harbingers of tumors at risk of progressing to t-NEPC after hormonal therapy.
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Circulating Tumor Cells from Prostate Cancer Patients Interact with E-Selectin under Physiologic Blood Flow.
PLoS ONE
PUBLISHED: 01-01-2013
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Hematogenous metastasis accounts for the majority of cancer-related deaths, yet the mechanism remains unclear. Circulating tumor cells (CTCs) in blood may employ different pathways to cross blood endothelial barrier and establish a metastatic niche. Several studies provide evidence that prostate cancer (PCa) cell tethering and rolling on microvascular endothelium via E-selectin/E-selectin ligand interactions under shear flow theoretically promote extravasation and contribute to the development of metastases. However, it is unknown if CTCs from PCa patients interact with E-selectin expressed on endothelium, initiating a route for tumor metastases. Here we report that CTCs derived from PCa patients showed interactions with E-selectin and E-selectin expressing endothelial cells. To examine E-selectin-mediated interactions of PCa cell lines and CTCs derived from metastatic PCa patients, we used fluorescently-labeled anti-prostate specific membrane antigen (PSMA) monoclonal antibody J591-488 which is internalized following cell-surface binding. We employed a microscale flow device consisting of E-selectin-coated microtubes and human umbilical vein endothelial cells (HUVECs) on parallel-plate flow chamber simulating vascular endothelium. We observed that J591-488 did not significantly alter the rolling behavior in PCa cells at shear stresses below 3 dyn/cm(2). CTCs obtained from 31 PCa patient samples showed that CTCs tether and stably interact with E-selectin and E-selectin expressing HUVECs at physiological shear stress. Interestingly, samples collected during disease progression demonstrated significantly more CTC/E-selectin interactions than samples during times of therapeutic response (p=0.016). Analysis of the expression of sialyl Lewis X (sLe(x)) in patient samples showed that a small subset comprising 1.9-18.8% of CTCs possess high sLe(x) expression. Furthermore, E-selectin-mediated interactions between prostate CTCs and HUVECs were diminished in the presence of anti-E-selectin neutralizing antibody. CTC-Endothelial interactions provide a novel insight into potential adhesive mechanisms of prostate CTCs as a means to initiate metastasis.
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Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen monoclonal antibody j591 in men with metastatic castration-resistant prostate cancer.
Front Oncol
PUBLISHED: 01-01-2013
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Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkins lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing (177)Lu- or (90)Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT.
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Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets.
Cancer Discov
PUBLISHED: 12-15-2011
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Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells. There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment. We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC, and future clinical trials will help determine from the efficacy of Aurora kinase inhibitor therapy.
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A phase I trial of sorafenib plus gemcitabine and capecitabine for patients with advanced renal cell carcinoma: New York Cancer Consortium Trial NCI 6981.
Am. J. Clin. Oncol.
PUBLISHED: 12-13-2011
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To define the safety [dose limiting toxicity (DLT)] and recommended phase II dose of the combination of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC).
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Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer.
Eur. Urol.
PUBLISHED: 09-16-2011
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We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes.
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Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1?.
Cancer Res.
PUBLISHED: 09-09-2011
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Renal cancers are highly aggressive and clinically challenging, but a transgenic mouse model to promote pathologic studies and therapeutic advances has yet to be established. Here, we report the generation of a transgenic mouse model of von Hippel-Lindau (VHL) renal cancer termed the TRACK model (transgenic model of cancer of the kidney). TRACK mice specifically express a mutated, constitutively active HIF1? in kidney proximal tubule (PT) cells. Kidney histologies displayed by TRACK mice are highly similar to histologies seen in patients with VHL disease, including areas of distorted tubular structure, cells with clear cytoplasm and increased glycogen and lipid deposition, multiple renal cysts, and early onset of clear cell renal cell carcinoma (ccRCC). Distorted tubules in TRACK mice exhibit higher levels of CA-IX, Glut1, and VEGF than tubules in nontransgenic control mice. Furthermore, these tubules exhibit increased numbers of endothelial cells, increased cell proliferation, and increased expression of the human ccRCC marker CD70(TNFSF7). Moreover, PT cells in kidney tubules from TRACK mice exhibit increased genomic instability, as monitored by elevated levels of ?H2AX. Our findings establish that activated HIF1? in murine kidney PT cells is sufficient to promote cell proliferation, angiogenesis, genomic instability, and other phenotypic alterations characteristic of human VHL kidney disease, establishing the TRACK mouse as a valid preclinical model of human renal cell carcinoma.
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Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer.
Cancer Res.
PUBLISHED: 07-28-2011
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Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired ?-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy.
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Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993 to 2002), stage and grade (1993 to 2007).
J. Urol.
PUBLISHED: 03-21-2011
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Bladder cancer survival is consistently lower in female and black patients than in male and white patients. We compared trends and differences according to clinical, demographic and facility characteristics by patient race and gender to identify the impact of these characteristics on survival.
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A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802.
Med. Oncol.
PUBLISHED: 01-04-2011
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Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis. Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of doxorubicin 50 mg/m(2) IV push and gemcitabine 1,500 mg/m(2) IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features. Ten patients (26%) had grade 3 toxicity, and four patients (11%) had grade 4 toxicities. Although most toxicity was from myelosuppression, one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m(2) doxorubicin. Six (16%) patients experienced responses (5 partial responses and 1 complete response), and ten (26%) patients had stable disease. In addition, another patient had an unconfirmed partial response and an additional patient experienced over 50% decrease in her tumor burden after an initial progression. The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and gemcitabine, inactive in patients with mostly clear cell histology, demonstrated responses in patients with RCC with sarcomatoid features. We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology. Only through prospective multicenter trials with comprehensive central pathology review will better treatment options be identified.
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Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy.
Med. Oncol.
PUBLISHED: 07-29-2010
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Sarcomatoid renal cell cancer is associated with a very poor prognosis, characterized by rapid progression of advanced disease. We previously reported the outcome of 18 patients with advanced sarcomatoid renal cell cancer treated with a regimen consisting of doxorubicin, 50 mg/m2 and gemcitabine, 1,500-2,000 mg/m2, administered every two weeks with growth factor support (A/G). Among the 18 patients, there were two complete and 5 partial responses and two patients with stable disease of more than 6 months of duration. We now report long-term survival of 4 patients with stage IV sarcomatoid renal cell carcinoma treated with this regimen at the 1,500 mg/m2 dose of gemcitabine, and achieving complete response (2 patients), or rendered complete responders following surgery after maximum response (2 patients). The two complete responders are alive, disease free at 6+ and 8+ years after starting A/G, and the 2 patients rendered CR by surgery survived 3½ and 6 years, respectively. Both died of progressive disease, one with clear cell recurrence, one with sarcomatoid recurrence. In summary, this regimen is associated with a high response rate, overall improvement in progression free survival and occasional meaningful long-term survival in a disease expected to be fatal within one year.
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Phase I trial of ATRA-IV and Depakote in patients with advanced solid tumor malignancies.
Cancer Biol. Ther.
PUBLISHED: 05-08-2010
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Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity
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Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer.
Urol. Oncol.
PUBLISHED: 05-07-2010
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Docetaxel is considered first-line chemotherapy for patients with metastatic castrate resistant prostate cancer (CRPC). Carboplatin and paclitaxel have demonstrated activity in CRPC but published data are limited regarding use after docetaxel.
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Anti-prostate-specific membrane antigen-based radioimmunotherapy for prostate cancer.
Cancer
PUBLISHED: 02-04-2010
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Despite recent advances, advanced prostate cancer is suboptimally responsive to current chemotherapeutic agents. Radiolabeled monoclonal antibody therapy that targets prostate-specific membrane antigen (PSMA) shows promise and is an area of active investigation. J591 is a deimmunized IgG monoclonal antibody developed to target the extracellular domain of PSMA. Preclinical and early phase clinical studies using radiolabeled J591 have demonstrated efficacy in targeting tumor cells and decreasing levels of prostate-specific antigen. Radiolabeled J591 is well-tolerated, nonimmunogenic, and can be administered in multiple doses. The dose-limiting toxicity is reversible myelosuppression with little nonhematologic toxicity. Future studies will include approaches to optimize patient selection and incorporate novel strategies to improve the success of anti-PSMA radioimmunotherapy.
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Recent advances in management of renal cancer.
F1000 Med Rep
PUBLISHED: 11-26-2009
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Therapeutic options for patients with metastatic renal cell carcinoma have significantly improved over the past few years, resulting in prolonged progression-free and overall survival.
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Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody.
Lab Chip
PUBLISHED: 11-16-2009
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Geometrically enhanced differential immunocapture (GEDI) and an antibody for prostate-specific membrane antigen (PSMA) are used for high-efficiency and high-purity capture of prostate circulating tumor cells from peripheral whole blood samples of castrate-resistant prostate cancer patients.
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Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations.
J. Neurosci.
PUBLISHED: 08-07-2009
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A central question in Alzheimers disease research is what role synaptic activity plays in the disease process. Synaptic activity has been shown to induce beta-amyloid peptide release into the extracellular space, and extracellular beta-amyloid has been shown to be toxic to synapses. We now provide evidence that the well established synaptotoxicity of extracellular beta-amyloid requires gamma-secretase processing of amyloid precursor protein. Recent evidence supports an important role for intraneuronal beta-amyloid in the pathogenesis of Alzheimers disease. We show that synaptic activity reduces intraneuronal beta-amyloid and protects against beta-amyloid-related synaptic alterations. We demonstrate that synaptic activity promotes the transport of the amyloid precursor protein to synapses using live cell imaging, and that the protease neprilysin is involved in reduction of intraneuronal beta-amyloid with synaptic activity.
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Final results of sequential doxorubicin plus gemcitabine and ifosfamide, paclitaxel, and cisplatin chemotherapy in patients with metastatic or locally advanced transitional cell carcinoma of the urothelium.
J. Clin. Oncol.
PUBLISHED: 07-27-2009
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Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity.
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Neutral endopeptidase is a myristoylated protein.
Mol. Cell. Biochem.
PUBLISHED: 04-28-2009
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Neutral endopeptidase (NEP) is a cell-surface peptidase normally expressed by prostate epithelial cells and lost in ~50% of primary prostate cancers. NEP directly associates with multiple proteins at the cell surface including Ezrin/Radixin/Moesin (ERM) proteins and the PTEN tumor suppressor protein. Analysis of the N-terminal sequence of the NEP cytosolic domain (N-terminal MGKSESQMDI TDINTPKPKK KQRWTR) identified a myristoylation consensus site. Mutation of Gly-2 to Arg significantly decreased (3)H-myristoylation activity, and correlated with translocation of NEP from the plasma membrane to a perinuclear domain as demonstrated by immunofluorescence staining and Western blotting with an NEP-specific antibody. Removal of this myristoylation residue did not affect NEP enzymatic specific activity. Myristoylated NEP recruited more PTEN protein to the cell membrane fraction than unmyristoylated NEP. These data demonstrate that NEP is myristoylated at Gly-2 and that this modification is an intrinsic signal for membrane targeting.
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Rational redesign of neutral endopeptidase binding to merlin and moesin proteins.
Protein Sci.
PUBLISHED: 04-24-2009
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Neutral endopeptidase (NEP) is a 90- to 110-kDa cell-surface peptidase that is normally expressed by numerous tissues but whose expression is lost or reduced in a variety of malignancies. The anti-tumorigenic function of NEP is mediated not only by its catalytic activity but also through direct protein-protein interactions of its cytosolic region with several binding partners, including Lyn kinase, PTEN, and ezrin/radixin/moesin (ERM) proteins. We have previously shown that mutation of the K(19)K(20)K(21) basic cluster in NEPs cytosolic region to residues QNI disrupts binding to the ERM proteins. Here we show that the ERM-related protein merlin (NF2) does not bind NEP or its cytosolic region. Using experimental data, threading, and sequence analysis, we predicted the involvement of moesin residues E(159)Q(160) in binding to the NEP cytosolic domain. Mutation of these residues to NL (to mimic the corresponding N(159)L(160) residues in the nonbinder merlin) disrupted moesin binding to NEP. Mutation of residues N(159)L(160)Y(161)K(162)M(163) in merlin to the corresponding moesin residues resulted in NEP binding to merlin. This engineered NEP peptide-merlin interaction was diminished by the QNI mutation in NEP, supporting the role of the NEP basic cluster in binding. We thus identified the region of interaction between NEP and moesin, and engineered merlin into a NEP-binding protein. These data form the basis for further exploration of the details of NEP-ERM binding and function.
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Carcinomatous meningitis in a patient with Her2/neu expressing bladder cancer following trastuzumab and chemotherapy: a case report and review of the literature.
J Med Case Rep
PUBLISHED: 04-08-2009
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Targeted therapies may impact the natural history of bladder cancer based upon their pharmacokinetics. The Her2/neu receptor tyrosine kinase, overexpressed by half of all primary urothelial carcinomas, has recently been examined as a therapeutic target in bladder cancer in a prospective phase II multicenter trial (NCI-198) that enrolled 109 patients with advanced bladder carcinomas for treatment with trastuzumab in combination with paclitaxel, carboplatin, and gemcitabine. We report on documented isolated Her2/neu positive carcinomatous meningitis in a patient treated with trastuzumab.
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Surveillance of urothelial carcinoma: stage and grade migration, 1993-2005 and survival trends, 1993-2000.
Cancer
PUBLISHED: 02-14-2009
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Previous investigators have detected shifts to lower stages at diagnosis for renal cell carcinoma and prostate cancer. The authors investigated whether a similar pattern is seen for urothelial carcinomas of the bladder, ureter, and renal pelvis and sought to identify changes in cancer grade and survival trends from 1993 to 2005.
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Endothelin-1 enhances the expression of the androgen receptor via activation of the c-myc pathway in prostate cancer cells.
Mol. Carcinog.
PUBLISHED: 02-13-2009
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Increasing evidence suggests that androgen independent prostate cancer (PC) maintains a functional androgen receptor (AR) pathway despite the low levels of circulating androgen following androgen withdrawal, the molecular mechanisms of which are not well defined yet. To address this question, we investigated the effects of endothelin-1 (ET-1) on AR expression. Western analysis and RT-PCR revealed that in the presence of ET-1, levels of AR significantly increased in a time- and dose-dependent manner in LNCaP cells. Pretreatments with inhibitors of Src and phosphoinositide kinase 3 (PI-3K) suppressed ET-1-induced AR expression. As ET-1 was reported to cause a transient increase in c-myc mRNA levels, we examined the involvement of c-myc in ET-1-mediated AR expression. Transient transfection of c-myc siRNA neutralized ET-1-induced AR expression, suggesting that AR induction by ET-1 is c-myc dependent. AR can regulate the transcription of its own gene via a mechanism in which c-myc plays a crucial role. Therefore, we assessed if ET-1-induced-c-myc leads to the enhancement of AR transcription. Reporter gene assays using the previously identified AR gene enhancer containing a c-myc binding site were conducted in LNCaP cells. We found that ET-1 induced reporter gene activity from the construct containing the wild-type but not mutant c-myc binding site. Chromatin immunoprecipitation assays confirmed that ET-1 increased interaction between c-myc and c-myc binding sites in AR enhancer, suggesting that ET-1-induced AR transcription occurs via c-myc-mediated AR transcription. Together, these data support the notion that ET-1, via Src/PI-3K signaling, augments c-myc expression leading to enhanced AR expression in PC.
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Negative regulation of NEP expression by hypoxia.
Prostate
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Neutral endopeptidase (NEP) is a transmembrane cell surface peptidase present on prostatic epithelial cells that catalytically inactivates small peptide substrates. Neutral endopeptidase loss is associated with prostate cancer growth, progression, and increased angiogenesis. We examined whether NEP expression is regulated by hypoxia, frequently encountered in the tumor microenvironment.
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Isolation and characterization of circulating tumor cells in prostate cancer.
Front Oncol
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Circulating tumor cells (CTCs) are tumor cells found in the peripheral blood that putatively originate from established sites of malignancy and likely have metastatic potential. Analysis of CTCs has demonstrated promise as a prognostic marker as well as a source of identifying potential targets for novel therapeutics. Isolation and characterization of these cells for study, however, remain challenging owing to their rarity in comparison with other cellular components of the peripheral blood. Several techniques that exploit the unique biochemical properties of CTCs have been developed to facilitate their isolation. Positive selection of CTCs has been achieved using microfluidic surfaces coated with antibodies against epithelial cell markers or tumor-specific antigens such as EpCAM or prostate-specific membrane antigen (PSMA). Following isolation, characterization of CTCs may help guide clinical decision making. For instance, molecular and genetic characterization may shed light on the development of chemotherapy resistance and mechanisms of metastasis without the need for a tissue biopsy. This paper will review novel isolation techniques to capture CTCs from patients with advanced prostate cancer, as well as efforts to characterize the CTCs. We will also review how these analyzes can assist in clinical decision making. Conclusion: The study of CTCs provides insight into the molecular biology of tumors of prostate origin that will eventually guide the development of tailored therapeutics. These advances are predicated on high yield and accurate isolation techniques that exploit the unique biochemical features of these cells.
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Androgen receptor on the move: boarding the microtubule expressway to the nucleus.
Cancer Res.
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Recent studies have shown that the microtubule-stabilizing drug paclitaxel, which is commonly used for the treatment of prostate cancer, inhibits signaling from the androgen receptor by inhibiting its nuclear accumulation downstream of microtubule stabilization. This mechanism is independent of paclitaxel-induced mitotic arrest and could provide an alternative mechanism of drug action that can explain its clinical activity. In this review, we highlight the importance of signaling and trafficking pathways that depend on intact and dynamic microtubules, and, as such, they represent downstream targets of microtubule inhibitors. We showcase prostate cancer, which is driven by the activity of the androgen receptor, as recent reports have revealed a connection between the microtubule-dependent trafficking of the androgen receptor and the clinical efficacy of taxanes. Identification and further elucidation of microtubule-dependent tumor-specific pathways will help us better understand the molecular basis of clinical taxane resistance as well as to identify individual patients more likely to respond to treatment.
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Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity.
Eur. Urol.
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Most personalized cancer care strategies involving DNA sequencing are highly reliant on acquiring sufficient fresh or frozen tissue. It has been challenging to comprehensively evaluate the genome of advanced prostate cancer (PCa) because of limited access to metastatic tissue.
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Adenoviral neutral endopeptidase gene delivery in combination with paclitaxel for the treatment of prostate cancer.
Int. J. Oncol.
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Neutral endopeptidase (NEP) is a cell-surface peptidase that inhibits prostate cancer cell growth partly via inhibition of Akt kinase. We investigated the antitumor effects of an adenovirus gene delivery system (AdNEP) to restore NEP expression in DU145 prostate cancer cells in combination with paclitaxel chemotherapy. DU145 cells were infected with adenovirus expressing NEP or LacZ, treated with paclitaxel, and assessed for cell viability, Akt activation and induction of apoptosis. Athymic mice with established DU145 xenografts were injected intratumorally with AdNEP or AdLacZ and intraperitoneally with paclitaxel and monitored for tumor growth over 28 days. Compared to AdLacZ plus paclitaxel, AdNEP plus paclitaxel significantly inhibited DU145 cell growth and increased apoptosis as determined by increased caspase-3 and PARP-1 proteolytic fragments. In a xenograft model, tumor volume was reduced in mice treated with AdNEP plus paclitaxel (122.85±89.5 mm3; P<0.01) compared with mice treated with AdNEP plus saline (653.9±230.3 mm3), AdLacZ plus paclitaxel (575.9±176.6 mm3) or AdLacZ plus saline (920.2±238.2 mm3). In conclusion, these data suggest that NEP can augment taxane-induced apoptosis through inhibition of Akt/Bad signaling, and that the combination of NEP plus paclitaxel may be an effective strategy to inhibit castration-resistant prostate cancer growth.
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Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device.
PLoS ONE
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Cancer metastasis accounts for the majority of cancer-related deaths owing to poor response to anticancer therapies. Molecular understanding of metastasis-associated drug resistance remains elusive due to the scarcity of available tumor tissue. Isolation of circulating tumor cells (CTCs) from the peripheral blood of patients has emerged as a valid alternative source of tumor tissue that can be subjected to molecular characterization. However, issues with low purity and sensitivity have impeded adoption to clinical practice. Here we report a novel method to capture and molecularly characterize CTCs isolated from castrate-resistant prostate cancer patients (CRPC) receiving taxane chemotherapy. We have developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that combines an anti-prostate specific membrane antigen (PSMA) antibody with a 3D geometry that captures CTCs while minimizing nonspecific leukocyte adhesion. Enumeration of GEDI-captured CTCs (defined as intact, nucleated PSMA+/CD45- cells) revealed a median of 54 cells per ml identified in CRPC patients versus 3 in healthy donors. Direct comparison with the commercially available CellSearch® revealed a 2-400 fold higher sensitivity achieved with the GEDI device. Confocal microscopy of patient-derived GEDI-captured CTCs identified the TMPRSS2:ERG fusion protein, while sequencing identified specific androgen receptor point mutation (T868A) in blood samples spiked with only 50 PC C4-2 cells. On-chip treatment of patient-derived CTCs with docetaxel and paclitaxel allowed monitoring of drug-target engagement by means of microtubule bundling. CTCs isolated from docetaxel-resistant CRPC patients did not show any evidence of drug activity. These measurements constitute the first functional assays of drug-target engagement in living circulating tumor cells and therefore have the potential to enable longitudinal monitoring of target response and inform the development of new anticancer agents.
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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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