The treatment for malignant glioma (glioblastoma) remains a challenge. Several experimental paradigms continue to be utilized in clinical trials, such as oncolytic viruses (OV), engineered or naturally occurring virus strains that replicate selectively in tumors. Oncolytic herpes simplex virus type 1 (oHSV) clinical trials have revealed its safety in humans with malignant gliomas, but more work is required to increase its efficacy. The investigators of this program project thus hypothesize that oHSV replication and dispersal in glioblastoma is curtailed by multiple oHSV-based and host-based barriers and responses during the very initial phases of viral infection and replication {aim 1). Understanding the nature of these barriers and responses would allow us to exploit both pharmacologic and genetic modalities to circumvent oHSV-based and host-based barriers and responses and increase the efficacy of malignant glioma virotherapy (aim 2). To achieve these aims, project 1 (PI: J. Glorioso) plans to re-engineer oHSV to redirect it towards glioma cell surface receptors while increasing its safety using microRNA-based translational controls of oHSV genes;Project 2 (PI: E.A. Chiocca) will characterize a novel mechanism of antiviral action within tumor cells that is based on one of the histone deacetylases, HDAC6, how it interacts with Interferon and how it shuttles post-entry oHSV towards lysosomes for xenophagy rather than nucleus for active replication;Project 3 (PI: B. Kaur) will determine how the stroma of the tumor microenvironment impedes oHSV dispersal and will utilize chondroitinase to counteract this;Project 4 (PI: M.A. Caligiuri) will show how the rapid NK cell activation against virally infected nervous system tumors is deleterious to therapy and will characterize the cellular and molecular effectors of this response. These 5 projects will be served by the unique resources provided by Core A (Biostatistics/ Administration: Chiocca/Fernadez) that provides biostatistical justification for al projects, Core B (oHSV Production: Goins) that provides all projects with the same stock of purified oHSV and Core C (Glioma Biorepository: Nakano) that provides all projects with patient-derived glioma spheroids (GSs) that recapitulate the human tumor phenotypic/genetic features.

Public Health Relevance

oHSV-based clinical trials of malignant gliomas have been well tolerated by humans, but more work is required to enhance the efficacy of the treatment. This program project will characterize fundamental barriers and host responses that are deleterious to the efficacy of oHSV and will provide solutions that will increase oHSV therapeutic effectiveness, while maintaining its current record of safety.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (O1))
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Ogunbiyi, Peter
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Ohio State University
Schools of Medicine
United States
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Mazzacurati, Lucia; Marzulli, Marco; Reinhart, Bonnie et al. (2015) Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV. Mol Ther 23:99-107
Nakashima, Hiroshi; Nguyen, Tran; Goins, William F et al. (2015) Interferon-stimulated gene 15 (ISG15) and ISG15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (HDAC6) and SQSTM1/p62. J Biol Chem 290:1485-95
Meisen, Walter Hans; Dubin, Samuel; Sizemore, Steven T et al. (2015) Changes in BAI1 and nestin expression are prognostic indicators for survival and metastases in breast cancer and provide opportunities for dual targeted therapies. Mol Cancer Ther 14:307-14
Bolyard, Chelsea; Yoo, Ji Young; Wang, Pin-Yi et al. (2014) Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer. Clin Cancer Res 20:6479-94
Nakano, Ichiro (2014) Proneural-mesenchymal transformation of glioma stem cells: do therapies cause evolution of target in glioblastoma? Future Oncol 10:1527-30
Bronisz, Agnieszka; Wang, Yan; Nowicki, Michal O et al. (2014) Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res 74:738-50
Nakashima, Hiroshi; Chiocca, E Antonio (2014) Switching a replication-defective adenoviral vector into a replication-competent, oncolytic adenovirus. J Virol 88:345-53
Kaufmann, Johanna K; Chiocca, E Antonio (2014) Glioma virus therapies between bench and bedside. Neuro Oncol 16:334-51
Wojton, Jeffrey; Meisen, Walter Hans; Jacob, Naduparambil K et al. (2014) SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma. Oncotarget 5:9703-9
Ganguly, Ranjit; Hong, Christopher S; Smith, Luke G F et al. (2014) Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers. Mol Cancer Ther 13:1393-8

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