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  • 1
    Keywords: CANCER ; GENOME ; PATHWAYS ; THERAPY ; GENE ; BREAST-CANCER ; prognosis ; MUTATION ; DATABASE ; MUTATIONS ; SOMATIC MUTATIONS ; tumours ; Type ; LANDSCAPES ; MYELOID-LEUKEMIA GENOME ; PROJECT ; CANCER-THERAPY ; MANAGEMENT ; SUBTYPES ; REPERTOIRE ; SCIENCE ; development
    Abstract: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies
    Type of Publication: Miscellaneous publication
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  • 2
    Keywords: APOPTOSIS ; THERAPY ; resistance ; GEMCITABINE ; CANCER PROGRESSION ; liver metastasis ; RIBOSOME-INACTIVATING PROTEINS ; pancreatic ductal adenocarcinoma ; XIMENIA-AMERICANA
    Abstract: Riproximin (Rpx) is a type II ribosome inactivating protein, which was investigated for its activity in pancreatic ductal adenocarcinoma (PDAC) in a panel of 17 human and rat PDAC cell lines and in rat pancreatic cancer liver metastasis. Cytotoxicity in response to Rpx was determined by MTT assay, apoptosis by flow cytometry and qRT-PCR for apoptosis related genes, and the modulation of the transcriptome was monitored by micro array analysis. The combination effect of Rpx and TRAIL was assessed by MTT assay. Rpx showed high but varying cytotoxicity in PDAC cells. Based on overall gene expression, the sensitivity of these cells was linked to genes involved in apoptosis. Furthermore, based on the affinity of Rpx for CEA, the expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) genes was significantly related to Rpx's cytotoxicity in cells with CEACAM gene expression.
    Type of Publication: Journal article published
    PubMed ID: 24918923
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  • 3
    Keywords: EXPRESSION ; THERAPY ; NF-KAPPA-B ; DENDRITIC CELLS ; ACTIVATED PROTEIN-KINASE ; CANCER-PATIENTS ; RHEUMATOID-ARTHRITIS ; p38 MAPK ; tumor microenvironment ; CHEMOTHERAPEUTIC-AGENTS ; NONCYTOTOXIC CONCENTRATIONS ; RET TRANSGENIC MICE
    Abstract: The antitumor effects of paclitaxel are generally attributed to the suppression of microtubule dynamics resulting in defects in cell division. New data demonstrated that in ultralow noncytotoxic concentrations, paclitaxel modulated in immune cells in vitro the activity of small Rho GTPases, the key regulators of intracellular actin dynamics. However, the immunomodulatory properties of paclitaxel in vivo have not been evaluated. In this study, using the ret transgenic murine melanoma model, which mimics human cutaneous melanoma, we tested effects of ultralow noncytotoxic dose paclitaxel on functions of myeloid-derived suppressor cells (MDSCs), chronic inflammatory mediators, and T cell activities in the tumor microenvironment in vivo. Administration of paclitaxel significantly decreased accumulation and immunosuppressive activities of tumor-infiltrating MDSCs without alterations of the bone marrow hematopoiesis. This was associated with the inhibition of p38 MAPK activity, TNF-alpha and production, and S100A9 expression in MDSCs. The production of mediators of chronic inflammation in the tumor milieu also was diminished. Importantly, reduced tumor burden and increased animal survival upon paclitaxel application was mediated by the restoration of CD8 T cell effector functions. We suggest that the ability of paclitaxel in a noncytotoxic dose to block the immunosuppressive potential of MDSCs in vivo represents a new therapeutic strategy to downregulate immunosuppression and chronic inflammation in the tumor microenvironment for enhancing the efficacy of concomitant anticancer therapies.
    Type of Publication: Journal article published
    PubMed ID: 23359505
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  • 4
    Keywords: GROWTH ; INHIBITOR ; ADVANCED SOLID TUMORS ; PHASE-I ; THERAPY ; MALIGNANCIES ; CANCER-CELLS ; TUMOR-INITIATING CELLS ; 3 YEARS OLD ; BI 2536
    Abstract: Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition. Cancer Res; 73(22); 6734-44. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 24019381
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  • 5
    Keywords: THERAPY ; EFFICIENCY ; TRANSDUCTION ; GENE-TRANSFER ; PARTICLES ; VIRAL VECTORS ; HEMOPHILIA ; CAPSIDS ; LEBERS CONGENITAL AMAUROSIS ; VECTOR REFERENCE-STANDARDS
    Abstract: Abstract Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50x10(11) pt/ml; CI, 4.26x10(11) to 6.75x10(11) pt/ml), vector genomes (mean, 5.75x10(11) vg/ml; CI, 3.05x10(11) to 1.09x10(12) vg/ml), and infectious units (mean, 1.26x10(9) IU/ml; CI, 6.46x10(8) to 2.51x10(9) IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community.
    Type of Publication: Journal article published
    PubMed ID: 25275822
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  • 6
    Keywords: EXPRESSION ; SURVIVAL ; THERAPY ; SITES ; TRIAL ; PROGRESSION ; AMPLIFICATION ; MARKERS ; PREDICTION
    Abstract: BACKGROUND: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time "liquid biopsy" approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. METHODS: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch(R), Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch(R)). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan-Meier plots. RESULTS: One hundred seven patients (median age (range) 57 (33-81) years) were included. 100/107 (93 %) patients were followed-up for a median [95 % confidence interval (CI)] of 28.5 [25.1-40.1] months. Of 37/107 (35 %) CTC-HER2-positive patients only 10 (27 %) were PRIM-HER2-positive. 6/46 (13 %) patients were MET-HER2-positive; only 2/10 (20 %) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69 % and 74 %, respectively. Kaplan-Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95 % CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7-13.7] versus 4.34 [3.5-5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7-30.0] versus 8.7 [5.9-15.3] months; p = 0.287). CONCLUSIONS: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform "liquid biopsy" to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed.
    Type of Publication: Journal article published
    PubMed ID: 25972110
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  • 7
    Keywords: SURVIVAL ; THERAPY ; SYSTEM ; TRIAL ; IDENTIFICATION ; chemotherapy ; MARKERS ; PERIPHERAL-BLOOD ; DISEASE PROGRESSION
    Abstract: BACKGROUND: To prospectively assess circulating tumor cell (CTC) status at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C), and changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) for their utility in predicting response, progression-free (PFS) and overall survival (OS) in metastatic breast cancer (MBC). METHODS: CTCBL and CTC1C status was determined as negative (-) or positive (+) for 〈 5 or 〉/= 5 CTCs/7.5 ml blood using CellSearch (Veridex). CTCKIN was categorized as favorable (CTC1C-) or unfavorable (CTC1C+). Tumor response was to be assessed every 2-3 months using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Statistical analysis focused on the relation between CTC status and CTCKIN, and response, PFS, and OS. RESULTS: 133/393 (34%) patients enrolled were CTCBL+. CTC1C status after one cycle and radiological tumor response were assessed after median (range) periods of 1.2 (0.5-3.2) and 2.9 (0.5-4.8) months, respectively. 57/201 (28%) were CTC1C+. Median [95% confidence interval] PFS and OS (months) were significantly reduced in CTCBL+ vs. CTCBL- patients (PFS 4.7 [3.7-6.1] vs. 7.8 [6.4-9.2]; OS 10.4 [7.9-15.0] vs. 27.2 [22.3-29.9]), and for CTC1C+ vs. CTC1C- patients (PFS 4.3 [3.6-6.0] vs. 8.5 [6.6-10.4]; OS 7.7 [6.4-13.9] vs. 30.6 [22.6-not available]). Unfavorable CTCKIN was significantly associated with progressive disease. Multivariate Cox regression analysis revealed prognostic factors for shorter PFS (CTCBL+, persistent CTCs after one cycle, 〉/= 3rd-line therapy, and triple-negative receptor status) and shorter OS (CTCBL+, persistent CTCs after one cycle, bone-and-visceral/local metastases, 〉/= 3rd-line therapy, and triple-negative receptor status). CONCLUSIONS: CTCBL, CTC1C, and CTCKIN are predictive of outcome in MBC. Serial CTC enumeration is useful in tailoring systemic treatment of MBC. TRIAL REGISTRATION: Not applicable.
    Type of Publication: Journal article published
    PubMed ID: 25015676
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