Since oHSV's replicative ability is one of the variables that contribute to its antitumor efficacy, we have been searching for pharmacologic modulators that would enhance it. Our published data has found that histone deacetylase inhibitors (HDACi), such as valproic acid (VPA), enhance replication of oHSV in glioma cell lines. In our pilot data, we have found that this is valid, even in freshly excised gliomas, cultured as spheroids (GSs) in serum-free media in the presence of defined growth factors. In order to discover the reason for this, we have employed a specific inhibitor of one ofthe HDACs (HDAC6) and in pilot experiments have shown that we can replicate the effect of VPA, known to be a pan-HDACi. Interestingly, both specific inhibition of HDAC6 and pan-inhibition of HDACs revert type 1 interferon's (IFN) antiviral effect. Our pilot data appear to show a novel mechanism of antiviral signaling that routes incoming oHSVs to autophagosomes for xenophagy rather than to nuclei for replication. To confirm the role of HDAC6 as a novel antiviral signal and its inhibition of IFN antiviral action, we thus propose to: 1- Determine if inhibition of HDACS leads to enhanced oHSV replication in a panel of freshly excised human glioma spheroids (GSs) in vitro and in vivo, 2- Determine whether there is cross-talk between type 1 interferon signaling and HDAG6 activity in oHSV infected glioma cells and GS, and 3- Determine whether the observed antiviral function of HDAC6 relates to its action on oHSV endocytic trafficking. To perform this project, Core C will provide us GSs, Core B will provide purified lots of oHSVs, and Core A will provide the necessary biostatistical support. We will need to interact with Project 4 (Caligiuri) who has also discovered that HDACi inhibits NK cell generation of IFNy to correlate with our observed HDAC6 inhibition leading to improved oHSV replication and with Project 1 (Glorioso) and Dr. Cripe (collaborator) to determine the role of oHSV receptors and glioma receptor targeting in improving-entry and HDAC6-dependent post-entry events. We also provide critical information to Project 1 (Glorioso) for improvements in oHSV design and to Project 3 (Kaur) to determine whether HDACi will enhance replication of Chase-expressing oHSVs.

Public Health Relevance

; Treatment of glioblastoma with oHSVs has shown to be well tolerated in humans with encouraging efficacy. However, it is evident that efficacy will need further improvements for this therapy to be successful. The impact of our studies will show that modulation of oHSV therapy with FDA-approved drugs can be applied in the setting of current and planned clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163205-02
Application #
8694515
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$334,724
Indirect Cost
$114,183
Name
Ohio State University
Department
Type
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

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