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Text
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URL Address
<a href="http://doi.org/10.1093/neuonc/noz079" target="_blank" rel="noreferrer noopener">http://doi.org/10.1093/neuonc/noz079</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
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oHSV therapy increases trametinib access to brain tumors and sensitizes them in vivo
Publisher
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Neuro-Oncology
Date
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2019
2019-05
Subject
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glioblastoma (GBM); oncolytic herpes simplex virus-1 (oHSV); RAS-RAF-MEK-ERK signaling; Trametinib; Tumor necrosis factor α (TNFα)
Creator
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Yoo Ji Young; Swanner Jessica; Otani Yoshihiro; Nair Mitra; Park Flora; Banasavadi-Siddegowda Yeshavanth; Liu Joseph; Jaime-Ramirez Alena Cristina; Hong Bangxing; Geng Feng; Guo Deliang; Bystry Darlene; Pelphs Mitch; Quadri Haroon; Lee Tae Jin; Kaur Balveen
Description
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BACKGROUND: Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted HSV-1 viruses, but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. METHODS: Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. ELISA, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the anti-tumor efficacy. RESULT: oHSV treatment rescued trametinib-mediated feed-back reactivation of the MAPK signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penentration of trametnib after oHSV treatment. Trametinib, a MEK Kinase inhibitor, treatment led to a significant reduction in microglia- and macrophage-derived TNFα secretion in response to oHSV-treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T cell-mediated immunity, and increased survival in a glioma-bearing immune-competent mouse model. CONCLUSION: This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.
Identifier
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<a href="http://doi.org/10.1093/neuonc/noz079" target="_blank" rel="noreferrer noopener">10.1093/neuonc/noz079</a>
2019
Banasavadi-Siddegowda Yeshavanth
Bystry Darlene
Geng Feng
glioblastoma (GBM)
Guo Deliang
Hong Bangxing
Jaime-Ramirez Alena Cristina
June 2019 Update
Kaur Balveen
Lee Tae Jin
Liu Joseph
Nair Mitra
NEOMED College of Medicine
NEOMED College of Medicine Student
NEOMED Student Publications
Neuro-oncology
oncolytic herpes simplex virus-1 (oHSV)
Otani Yoshihiro
Park Flora
Pelphs Mitch
Quadri Haroon
RAS-RAF-MEK-ERK signaling
Swanner Jessica
Trametinib
Tumor necrosis factor α (TNFα)
Yoo Ji Young
-
Text
A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text.
URL Address
<a href="http://doi.org/10.1158/1535-7163.MCT-18-0953" target="_blank" rel="noreferrer noopener">http://doi.org/10.1158/1535-7163.MCT-18-0953</a>
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
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Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin beta1 Blocking Antibody OS2966.
Publisher
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Molecular cancer therapeutics
Date
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2019
2019-03
Creator
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Lee Tae Jin; Nair Mitra; Banasavadi-Siddegowda Yeshavanth Kumar; Liu Joseph; Nallanagulagari Tejaswini; Jaime-Ramirez Alena Cristina; Guo Jeffrey Yunhua; Quadri Haroon; Zhang Jianying; Bockhorst Kurt H; Aghi Manish K; Carbonell W Shawn; Kaur Balveen; Yoo Ji Young
Description
An account of the resource
Integrin beta1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression as well as resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin beta1 and was recently orphan designated by FDA Office of Orphan Products Development (OOPD). Here, we tested therapeutic potential of OS2966-mediated integrin beta1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and pro-inflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated anti-tumor efficacy in orthotopic xenograft models including triple negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve anti-tumor efficacy of conventional oHSV therapy.
Identifier
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<a href="http://doi.org/10.1158/1535-7163.MCT-18-0953" target="_blank" rel="noreferrer noopener">10.1158/1535-7163.MCT-18-0953</a>
2019
Aghi Manish K
Banasavadi-Siddegowda Yeshavanth Kumar
Bockhorst Kurt H
Carbonell W Shawn
Guo Jeffrey Yunhua
Jaime-Ramirez Alena Cristina
Kaur Balveen
Lee Tae Jin
Liu Joseph
Molecular cancer therapeutics
Nair Mitra
Nallanagulagari Tejaswini
NEOMED College of Medicine
NEOMED College of Medicine Student
NEOMED Student Publications
Quadri Haroon
Yoo Ji Young
Zhang Jianying