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Berlin Brandenburg

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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, 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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  • 3
    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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  • 4
    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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  • 5
    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...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    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...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 September 2014, Vol.20(18), pp.4894-903
    Description: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC). MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O(6)-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status. These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas.
    Keywords: DNA Methylation ; Promoter Regions, Genetic ; Brain Neoplasms -- Genetics ; DNA-Binding Proteins -- Genetics ; Drug Resistance, Neoplasm -- Genetics ; Glioblastoma -- Genetics ; Oligodendroglioma -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 8
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 November 2014, Vol.20(22), pp.5756-67
    Description: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor-initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ) EXPERIMENTAL DESIGN: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan-Meier survival studies were performed with AZD8055 and in combination with TMZ. We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival. These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs.
    Keywords: Brain Neoplasms -- Metabolism ; Dacarbazine -- Analogs & Derivatives ; Glioblastoma -- Metabolism ; Multiprotein Complexes -- Antagonists & Inhibitors ; Neoplastic Stem Cells -- Drug Effects ; Protein Kinase Inhibitors -- Pharmacology ; Tor Serine-Threonine Kinases -- Antagonists & Inhibitors
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 9
    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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  • 10
    In: Journal of the National Cancer Institute, 2006, Vol.98(21), pp.1546-1557
    Description: Background: An ideal virus for the treatment of cancer should have effective delivery into multiple sites within the tumor, evade immune responses, produce rapid viral replication, spread within the tumor, and infect multiple tumors. Vesicular stomatitis virus (VSV) has been shown to be an effective oncolytic virus in a variety of tumor models, and mutations in the matrix (M) protein enhance VSVs effectiveness in animal models. Methods: We evaluated the susceptibility of 14 glioma cell lines to infection and killing by mutant strain VSV M51 , which contains a singleamino acid deletion in the M protein. We also examined the activity and safety of this strain against the U87 and U118 experimental models of human malignant glioma in nude mice and analyzed the distribution of the virus in the brains of U87 tumorbearing mice using fluorescence labeling. Finally, we examined the effect of VSV M51 on 15 primary human gliomas cultured from surgical specimens. All statistical tests were two-sided. Results: All 14 glioma cell lines were susceptible to VSV M51 infection and killing. Intratumoral administration of VSV M51 produced marked regression of malignant gliomas in nude mice. When administered systemically, live VSV M51 virus, as compared with dead virus, statistically significantly prolonged survival of mice with unilateral U87 tumors (median survival: 113 versus 46 days, P .0001) and bilateral U87 tumors (median survival: 73 versus 46 days, P .0025). VSV M51 infected multifocal gliomas, invasive glioma cells that migrated beyond the main glioma, and all 15 primary human gliomas. There was no evidence of toxicity. Conclusions: Systemically delivered VSV M51 was an effective and safe oncolytic agent against laboratory models of multifocal and invasive malignant gliomas, the most challenging clinical manifestations of this disease.
    Keywords: Invasiveness ; Fluorescence ; Double Prime M Protein ; Replication ; Animal Models ; Statistical Analysis ; Tumors ; Toxicity ; Infection ; Brain Tumors ; Glioma Cells ; Oncolysis ; Glioma ; Mutation ; Vesicular Stomatitis Virus ; Genetic Engineering ; Viruses ; Medical Treatment ; Cancer ; Genetic Recombination ; Proteins ; Mutation ; Rodents;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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