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Berlin Brandenburg

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  • 1
    Language: English
    In: Future oncology (London, England), 2015, Vol.11(3), pp.535-42
    Description: Osteosarcoma and Ewing's sarcoma, the two most frequent malignant primary tumors preferentially arise in children and young adults, and have a poor prognosis. TRAIL represents a promising therapeutic approach for most cancers but in the case of primary bone tumors, osteosarcoma cell lines are highly resistant to this pro-apoptotic cytokine. In addition, another signaling pathway mediating cell proliferation and migration may be even activated in this subset of resistant cells leading to protumoral effect. Therapeutic perspectives are linked to possibility to overcome TRAIL resistance by combining other drugs with TRAIL or death receptors agonistic antibodies. We hypothesized that the bone microenvironment may provide a favorable niche for TRAIL resistance that might be targeted by new resensitizing agents.
    Keywords: Ewing'S Sarcoma ; Trail ; Microenvironment ; Osteosarcoma ; Resistance ; Molecular Targeted Therapy ; Antineoplastic Agents -- Therapeutic Use ; Bone Neoplasms -- Drug Therapy ; Signal Transduction -- Drug Effects ; Tnf-Related Apoptosis-Inducing Ligand -- Metabolism
    ISSN: 14796694
    E-ISSN: 1744-8301
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  • 2
    In: International Journal of Cancer, 15 December 2016, Vol.139(12), pp.2802-2811
    Description: Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro‐apoptotic cytokine TNF‐Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL‐induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full‐length human TRAIL were co‐cultured with several human EWS cell lines, inducing apoptosis by cell‐to‐cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell‐based delivery of a potent apoptosis‐inducing factor could be relevant in EWS. What's new? Ewing sarcoma is a highly metastatic bone tumor in children without major therapeutic advance in recent years. Here the authors tested the therapeutic benefit of the pro‐apoptotic cytokine TNF‐Related Apoptosis Inducing Ligand (TRAIL). Previous studies showed variable responses to recombinant TRAIL, and the authors hypothesized that TRAIL presented on the surface of mesenchymal stem cells (MSC) would show more consistent results. Indeed, TRAIL‐transfected MSCs induced apoptosis more reliably in Ewing sarcoma cell lines and in two orthotopic models, pointing to a cell‐based therapy as the more promising application for TRAIL in this cancer.
    Keywords: Trail ; Ewing Sarcoma ; Resistance ; Microenvironment ; Msc
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: American journal of cancer research, 2016, Vol.6(3), pp.677-89
    Description: Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients.
    Keywords: Osteosarcoma ; Bone Protection ; Inhibition of Lung Metastases Development ; Liposomal Mifamurtide ; Zoledronic Acid
    ISSN: 2156-6976
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 4
    Language: English
    In: Oncotarget, 15 September 2014, Vol.5(17), pp.7805-19
    Description: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50µg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma.
    Keywords: Antineoplastic Combined Chemotherapy Protocols -- Pharmacology ; Bone Neoplasms -- Pathology ; Clusterin -- Biosynthesis ; Diphosphonates -- Administration & Dosage ; Imidazoles -- Administration & Dosage ; Osteosarcoma -- Pathology ; Thionucleotides -- Administration & Dosage
    E-ISSN: 1949-2553
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  • 5
    Language: English
    In: Journal of Clinical Oncology, 05/20/2014, Vol.32(15_suppl), pp.10048-10048
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: CrossRef
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  • 6
    In: Bone Abstracts, 09/05/2018
    ISSN: Bone Abstracts
    E-ISSN: 2052-1219
    Source: CrossRef
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  • 7
    Language: English
    In: Molecular cancer research : MCR, March 2012, Vol.10(3), pp.336-46
    Description: Ewing's sarcoma (ES) is a high-grade neoplasm arising in bones of children and adolescents. Survival rate decreases from greater than 50% to only 20% after 5 years for patients not responding to treatment or presenting metastases at diagnosis. TRAIL, which has strong antitumoral activity, is a promising therapeutic candidate. To address TRAIL sensitivity, 7 human ES cell lines were used. Cell viability experiments [3'[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro-)benzene sulfonic acid hydrate (XTT) assay] showed that 4 of the 7 ES cell lines were resistant to TRAIL. Western blotting and flow cytometry analyses revealed that DR5 was uniformly expressed by all ES cell lines, whereas DR4 levels were higher in sensitive cell lines. In TRAIL-sensitive TC-71 cells, knockdown of TNFRSF10A/DR4 by short hairpin RNA (shRNA) was associated with a loss of sensitivity to TRAIL, in spite of DR5 presence. Interestingly, we identified a new transcript variant that results from an alternative splicing and encodes a 310-amino acid protein which corresponds to the 468 aa of DR4 original isoform but truncated of aa 11 to 168 within the extracellular TRAIL-binding domain. According to modeling studies, the contact of this new DR4 isoform (bDR4) with TRAIL seemed largely preserved. The overexpression of bDR4 in a TRAIL-resistant cell line restored TRAIL sensitivity. TRAIL resensitization was also observed after c-FLIP knockdown by shRNA in two TRAIL-resistant cell lines, as shown by XTT assay and caspase-3 assay. The results presented in this study showed that DR4, both as the complete form or as its new short isoform, is involved in TRAIL sensitivity in ES.
    Keywords: Drug Resistance, Neoplasm -- Drug Effects ; Receptors, Tnf-Related Apoptosis-Inducing Ligand -- Metabolism ; Sarcoma, Ewing -- Metabolism ; Tnf-Related Apoptosis-Inducing Ligand -- Pharmacology
    ISSN: 15417786
    E-ISSN: 1557-3125
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  • 8
    Language: English
    In: American journal of cancer research / Am J Cancer Res, 15 February 2016, Vol.6, pp.677-689
    Description: Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in...
    Keywords: Life Sciences ; Human Health and Pathology ; Life Sciences ; Human Health and Pathology ; Pediatrics ; Life Sciences ; Cancer ; Inhibition of Lung Metastases Development ; Bone Protection ; Zoledronic Acid ; Osteosarcoma ; Liposomal Mifamurtide ; Medicine
    ISSN: 2156-6976
    E-ISSN: 2156-6976
    Source: Hyper Article en Ligne (CCSd)
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  • 9
    Language: English
    In: Cytotherapy, August 2018, Vol.20(8), pp.1037-1045
    Description: Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor. OS patients have not seen any major therapeutic progress in the last 30 years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine Tumor necrosis factor (TNF)–Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, many OS cell lines appear resistant to recombinant human (rh)TRAIL-induced apoptosis. We, therefore, hypothesized that TRAIL presentation at the membrane level of carrier cells might overcome this resistance and trigger apoptosis. To address this, human adipose mesenchymal stromal cells (MSCs) transfected in a stable manner to express membrane-bound full-length human TRAIL (mbTRAIL) were co-cultured with several human OS cell lines. This induced apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL. In contrast, mbTRAIL delivered by MSCs was not able to counteract tumor progression in this OS orthotopic model. This was partly due to the fact that MSCs showed a potential to support tumor development. Moreover, the expression of mbTRAIL did not show caspase activation in adjacent tumor cells.
    Keywords: Mesenchymal Stromal Cells ; Osteosarcoma ; Tumor Necrosis Factor (Tnf)–Related Apoptosis Inducing Ligand ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1465-3249
    E-ISSN: 1477-2566
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  • 10
    Language: English
    In: Acta Neuropathologica, 2018, Vol.135(5), pp.757-777
    Description: Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1 . They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.
    Keywords: Craniopharyngioma ; Odontogenesis ; Inflammasome ; IL1-β ; MAPK/ERK pathway ; Trametinib ; Paracrine signalling
    ISBN: 0040101818302
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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