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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163205-02
Application #
8616356
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Program Officer
Daschner, Phillip J
Project Start
2013-02-07
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,496,177
Indirect Cost
$267,464
Name
Ohio State University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro et al. (2016) Senescence from glioma stem cell differentiation promotes tumor growth. Biochem Biophys Res Commun 470:275-81
Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885
Chen, Xilin; Han, Jianfeng; Chu, Jianhong et al. (2016) A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 7:27764-77
Cheng, Peng; Wang, Jia; Waghmare, Indrayani et al. (2016) FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells. Cancer Res 76:7219-7230
Ricklefs, Franz; Mineo, Marco; Rooj, Arun K et al. (2016) Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity. Cancer Res 76:2876-81
Goins, William F; Hall, Bonnie; Cohen, Justus B et al. (2016) Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol 21:93-101
Yoo, Ji Young; Jaime-Ramirez, Alena Cristina; Bolyard, Chelsea et al. (2016) Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy. Clin Cancer Res 22:5265-5276
Freud, Aharon G; Keller, Karen A; Scoville, Steven D et al. (2016) NKp80 Defines a Critical Step during Human Natural Killer Cell Development. Cell Rep 16:379-91
Xiao, Run; Bergin, Stephen M; Huang, Wei et al. (2016) Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype. Cancer Immunol Res 4:488-97
Kim, Sung-Hak; Ezhilarasan, Ravesanker; Phillips, Emma et al. (2016) Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner. Cancer Cell 29:201-13

Showing the most recent 10 out of 80 publications