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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 26 January 2010, Vol.107(4), pp.1576-81
    Description: Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV(DeltaM51)), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV(DeltaM51) selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV(DeltaM51).
    Keywords: Glioma -- Metabolism ; Interferon Type I -- Biosynthesis ; Transcription Factors -- Metabolism ; Vesicular Stomatitis -- Metabolism ; Vesiculovirus -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Cancer research, 15 June 2017, Vol.77(12), pp.3231-3243
    Description: Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) in malignant glioma, but the mechanism of its activation is unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTIC to promote their growth. We demonstrate the proximal localization of TNC and BTIC in human glioblastoma specimens and in orthotopic murine xenografts of human BTIC implanted intracranially. In tissue culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTIC. Exogenously applied or autocrine TNC increased BTIC growth through an α2β1 integrin-mediated mechanism that elevated NOTCH ligand Jagged1 (JAG1). Microarray analyses and confirmatory PCR and Western analyses in BTIC determined that NOTCH signaling components including JAG1, ADAMTS15, and NICD1/2 were elevated in BITC after TNC exposure. Inhibition of γ-secretase and metalloproteinase proteolysis in the NOTCH pathway, or silencing of α2β1 integrin or JAG1, reduced the proliferative effect of TNC on BTIC. Collectively, our findings identified TNC as a pivotal initiator of elevated NOTCH signaling in BTIC and define the establishment of a TN-α2β1-JAG1-NOTCH signaling axis as a candidate therapeutic target in glioma patients. .
    Keywords: Brain Neoplasms -- Pathology ; Glioma -- Pathology ; Neoplastic Stem Cells -- Pathology ; Receptors, Notch -- Metabolism ; Tenascin -- Metabolism
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 3
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.LB-140-LB-140
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Cancer research, 15 December 2014, Vol.74(24), pp.7260-73
    Description: Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.
    Keywords: Oncolytic Virotherapy ; Brain Neoplasms -- Therapy ; Glioma -- Therapy ; Myxoma Virus -- Immunology
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 5
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.1558-1558
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, June 17, 2011, Vol.722(2), p.94(12)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.mrgentox.2010.05.006 Byline: Igor Koturbash (a), Franz J. Zemp (a), Igor Pogribny (b), Olga Kovalchuk (a) Keywords: MicroRNA; Cancer; Carcinogenesis; Genome instability Abbreviations: miRNA, microRNA; AGO, argonaute; miRNP, miRNA/AGO ribonucleoprotein; RISC, RNA-induced silencing complex; MRE, miRNA recognition element; CLL, chronic lymphocytic leukemia; BCL2, B-cell lymphoma 2; oncomiR, oncogenic miRNA; HOXD10, homeobox protein D10; TICs, tumor initiating cells; DHFR, dihydrofolate reductase gene; IR, ionizing radiation Abstract: Small non-coding RNAs-microRNAs, are potent negative regulators of gene expression. MicroRNAs are involved in multiple biological processes, metabolic regulation, including cell proliferation, differentiation, and programmed cell death. Since the dysregulation of these processes is a hallmark of cancer, microRNAs can be viewed as major contributors to the pathogenesis of cancer, including initiation and progression of cancer. This review focuses on microRNA biogenesis and function, and their role in cancer, metastasis, drug resistance, and tumorigenesis. Author Affiliation: (a) Department of Biological Sciences, University of Lethbridge, AB, Canada T1K3M4 (b) Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, United States Article History: Received 28 April 2010; Accepted 8 May 2010 Article Note: (footnote) [star] The views expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration.
    Keywords: Lymphomas -- Development And Progression ; Drug Resistance -- Development And Progression ; Leukemia -- Development And Progression ; Carcinogenesis -- Development And Progression ; Cancer Metastasis -- Development And Progression ; Gene Expression ; Biosynthesis ; Tetrahydrofolate Dehydrogenase ; Cancer Treatment
    ISSN: 1383-5718
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e66825
    Description: Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R gene product, a viral E3-ubiquitin ligase) and suppressing T cell killing of infected target cells. MHC I down-regulation, however, favors NK cell activation. Brain tumors including gliomas are characterized by high MHC I expression with impaired NK activity. We thus hypothesized that MYXV infection of glioma cells will promote NK cell-mediated recognition and killing of gliomas. We infected human gliomas with MYXV and evaluated their susceptibility to NK cell-mediated cytotoxicity. MYXV enhanced NK cell-mediated killing of glioma cells (U87 cells, MYXV vs. Mock: 51.73% vs. 28.63%, P = .0001, t test; U251 cells, MYXV vs. Mock: 40.4% vs. 20.03%, P .0007, t test). Using MYXV M153R targeted knockout (designated vMyx-M153KO) to infect gliomas, we demonstrate that M153R was responsible for reduced expression of MHC I on gliomas and enhanced NK cell-mediated antiglioma activity (U87 cells, MYXV vs. vMyx-M153KO: 51.73% vs. 25.17%, P = .0002, t test; U251 cells, MYXV vs. vMyx-M153KO: 40.4% vs. 19.27, P = .0013, t test). Consequently, NK cell-mediated lysis of established human glioma tumors in CB-17 SCID mice was accelerated with improved mouse survival (log-rank P = .0072). These results demonstrate the potential for combining MYXV with NK cells to effectively kill malignant gliomas.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e65801
    Description: Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1 (+/-) Trp53 (+/-) mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Radiation and Environmental Biophysics, 2011, Vol.50(4), pp.491-499
    Description: This review focuses on a number of recent studies that have examined changes in microRNA (miRNA) expression profiles in response to ionizing radiation and other forms of oxidative stress. In both murine and human cells and tissues, a number of miRNAs display significant alterations in expression levels in response to both direct and indirect radiation exposure. In terms of direct irradiation, or exposure to agents that induce oxidative stress, miRNA array analyses indicate that a number of miRNAs are up- and down-regulated and, in particular, the let-7 family of miRNAs may well be critical in the cellular response to oxidative stress. In bystander cells that are not directly irradiated, but close to, or share media with directly irradiated cells or tissues, the miRNA expression profiles are also altered, but are somewhat distinct from the directly irradiated cells. Based on the results of these numerous studies, as well as our own data presented here, we conclude that miRNA regulation is a critical step in the cellular response to radiation and oxidative stress and that future studies should elucidate the mechanisms through which this altered regulation affects cell metabolism.
    Keywords: Cancer Research -- Physiological Aspects ; Cancer Research -- Analysis ; Radiation (Physics) -- Physiological Aspects ; Radiation (Physics) -- Analysis ; Proteins -- Physiological Aspects ; Proteins -- Analysis;
    ISSN: 0301-634X
    E-ISSN: 1432-2099
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  • 10
    Language: English
    In: Nature neuroscience, January 2014, Vol.17(1), pp.46-55
    Description: Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.
    Keywords: Amphotericin B -- Pharmacology ; Antineoplastic Agents -- Pharmacology ; Brain Neoplasms -- Pathology ; Glioma -- Pathology ; Macrophages -- Physiology ; Microglia -- Physiology ; Tumor Cells, Cultured -- Drug Effects
    ISSN: 10976256
    E-ISSN: 1546-1726
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