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 #
5P01CA163205-03
Application #
8796165
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$370,514
Indirect Cost
$127,046
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Russell, Luke; Swanner, Jessica; Jaime-Ramirez, Alena Cristina et al. (2018) PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nat Commun 9:5006
Dai, Hong-Sheng; Caligiuri, Michael A (2018) Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. Front Immunol 9:183
Chen, Luxi; Youssef, Youssef; Robinson, Cameron et al. (2018) CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway. Immunity 49:464-476.e4
Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572
Kim, Yangjin; Yoo, Ji Young; Lee, Tae Jin et al. (2018) Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy. Proc Natl Acad Sci U S A 115:4927-4932
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Scoville, Steven D; Nalin, Ansel P; Chen, Luxi et al. (2018) Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 132:1792-1804
Chan, Wing Keung; Kang, Siwen; Youssef, Youssef et al. (2018) A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol Res 6:776-787
Nakashima, Hiroshi; Alayo, Quazim A; Penaloza-MacMaster, Pablo et al. (2018) Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells. Sci Rep 8:208
Marzulli, M; Mazzacurati, L; Zhang, M et al. (2018) A Novel Oncolytic Herpes Simplex Virus Design based on the Common Overexpression of microRNA-21 in Tumors. J Gene Ther 3:

Showing the most recent 10 out of 117 publications