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.
; 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.
|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|
Showing the most recent 10 out of 33 publications