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  • 1
    Language: English
    In: Pharmacology and Therapeutics, May 2017, Vol.173, pp.146-158
    Description: Pancreatic cancer is a cruel, progressive disease that is highly metastatic and barely treatable, a situation that is devastating for patients, family members, oncologists, clinicians and scientists. Open questions that need to be resolved by research into pancreatic cancer relate to its aggressiveness, the underlying molecular causes, the factors that promote tumor progression, the ways cancer cells interact with their environments, and whether more effective therapeutic options can be developed. Studies over the last 15 years have provided some partial answers, but in the absence of a real cure the main agenda remains: to identify new therapeutic targets, predictive markers and novel treatment strategies that would help the disease under control. These goals can be advanced by translational research based on clinically relevant and standardized protocols and more reliable disease models. This review gives an overview of the preclinical in vitro and in vivo models for pancreatic cancer that are currently available. The restrictions on applicability, strengths and limitations of various experimental platforms including 3D organoids, syngeneic xenografts and genetically engineered mice are considered with respect to the complexity of pancreating cancer. Patient-derived xenografts (PDX) presently offer the most promise for translational research, so a particular emphasis is placed on key features as preclinical models for pancreatic cancer and their advancement toward precise simulations of clinical problems.
    Keywords: Translational Research ; Preclinical Oncology ; Mouse Models ; Patient-Derived Xenografts ; Pancreatic Cancer ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0163-7258
    E-ISSN: 1879-016X
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  • 2
    In: PLoS ONE, 2014, Vol.9(5)
    Description: Background Large-scale genomic analyses of patient cohorts have revealed extensive heterogeneity between individual tumors, contributing to treatment failure and drug resistance. In malignant melanoma, heterogeneity is thought to arise as a consequence of the differentiation of melanoma-initiating cells that are defined by cell-surface markers like CD271 or CD133. Results Here we confirmed that the nerve growth factor receptor (CD271) is a crucial determinant of tumorigenicity, stem-like properties, heterogeneity and plasticity in melanoma cells. Stable shRNA mediated knock-down of CD271 in patient-derived melanoma cells abrogated their tumor-initiating and colony-forming capacity. A genome-wide expression profiling and gene-set enrichment analysis revealed novel connections of CD271 with melanoma-associated genes like CD133 and points to a neural crest stem cell (NCSC) signature lost upon CD271 knock-down. In a meta-analysis we have determined a shared set of 271 differentially regulated genes, linking CD271 to SOX10, a marker that specifies the neural crest. To dissect the connection of CD271 and CD133 we have analyzed 10 patient-derived melanoma-cell strains for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271 + cells in the majority of cell strains analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell strains harbored a CD133 + sub-set that in addition comprised a fraction of cells of a CD271 + /CD133 + phenotype. Those cells were found in the label-retaining fraction and in vitro deduced from CD271 + but not CD271 knock-down cells. Conclusions Our present study provides a deeper insight into the regulation of melanoma cell properties and points CD271 out as a regulator of several melanoma-associated genes. Further, our data strongly suggest that CD271 is a crucial determinant of stem-like properties of melanoma cells like colony-formation and tumorigenicity.
    Keywords: Research Article ; Biology And Life Sciences ; Medicine And Health Sciences
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Cancer Research, 07/01/2017, Vol.77(13 Supplement), pp.4943-4943
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.1463-1463
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.4080-4080
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: PLoS ONE, May 5, 2014, Vol.9(5)
    Description: Background Large-scale genomic analyses of patient cohorts have revealed extensive heterogeneity between individual tumors, contributing to treatment failure and drug resistance. In malignant melanoma, heterogeneity is thought to arise as a consequence of the differentiation of melanoma-initiating cells that are defined by cell-surface markers like CD271 or CD133. Results Here we confirmed that the nerve growth factor receptor (CD271) is a crucial determinant of tumorigenicity, stem-like properties, heterogeneity and plasticity in melanoma cells. Stable shRNA mediated knock-down of CD271 in patient-derived melanoma cells abrogated their tumor-initiating and colony-forming capacity. A genome-wide expression profiling and gene-set enrichment analysis revealed novel connections of CD271 with melanoma-associated genes like CD133 and points to a neural crest stem cell (NCSC) signature lost upon CD271 knock-down. In a meta-analysis we have determined a shared set of 271 differentially regulated genes, linking CD271 to SOX10, a marker that specifies the neural crest. To dissect the connection of CD271 and CD133 we have analyzed 10 patient-derived melanoma-cell strains for cell-surface expression of both markers compared to established cell lines MeWo and A375. We found CD271.sup.+ cells in the majority of cell strains analyzed as well as in a set of 16 different patient-derived melanoma metastases. Strikingly, only 2/12 cell strains harbored a CD133.sup.+ sub-set that in addition comprised a fraction of cells of a CD271.sup.+ /CD133.sup.+ phenotype. Those cells were found in the label-retaining fraction and in vitro deduced from CD271.sup.+ but not CD271 knock-down cells. Conclusions Our present study provides a deeper insight into the regulation of melanoma cell properties and points CD271 out as a regulator of several melanoma-associated genes. Further, our data strongly suggest that CD271 is a crucial determinant of stem-like properties of melanoma cells like colony-formation and tumorigenicity.
    Keywords: Drug Resistance – Analysis ; Nerve Growth Factor – Analysis ; Stem Cells – Analysis ; Genomics – Analysis
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.4093-4093
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 8
    Language: English
    In: Handbook of experimental pharmacology, 2016, Vol.232, pp.203-21
    Description: Experimental oncology research and preclinical drug development both substantially require specific, clinically relevant in vitro and in vivo tumor models. The increasing knowledge about the heterogeneity of cancer requested a substantial restructuring of the test systems for the different stages of development. To be able to cope with the complexity of the disease, larger panels of patient-derived tumor models have to be implemented and extensively characterized. Together with individual genetically engineered tumor models and supported by core functions for expression profiling and data analysis, an integrated discovery process has been generated for predictive and personalized drug development.Improved “humanized” mouse models should help to overcome current limitations given by xenogeneic barrier between humans and mice. Establishment of a functional human immune system and a corresponding human microenvironment in laboratory animals will strongly support further research.Drug discovery, systems biology, and translational research are moving closer together to address all the new hallmarks of cancer, increase the success rate of drug development, and increase the predictive value of preclinical models.
    Keywords: Drug Discovery ; Drug Screening Assays, Antitumor
    ISSN: 0171-2004
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 9
    Language: English
    In: Molecular Cancer Therapeutics, 12/2015, Vol.14(12 Supplement 2), pp.A100-A100
    ISSN: 1535-7163
    E-ISSN: 1538-8514
    Source: CrossRef
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  • 10
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 December 2016, Vol.22(24), pp.6153-6163
    Description: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients. We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically. Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors. This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153-63. ©2016 AACR.
    Keywords: DNA Helicases -- Metabolism ; DNA-Binding Proteins -- Metabolism ; Pancreatic Neoplasms -- Metabolism ; Proto-Oncogene Proteins C-Myc -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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