The overall goal of this project is to improve treatment of malignant gliomas using novel mutant HSV-1 Earlier studies showed that ionizing radiation (IR) activates expression of late HSV-1 genes, enabling better viral replication and enhancing the therapeutic value of Ayi34.5 HSV. In response to evidence that the effectiveness of Ayi34.5HSV is dependent on tumor cell gene expression, we identified a key host gene, MEK that overcomes the restriction to viral replication. Project 1 constructed a mutant virus (R2660) carrying a radio-inducible constitutively-acting MEK (caMEK) gene that overcomes tumor resistance to HSV.
In Aim 1, we propose to determine the radiation dose for optimum expression of the MEK gene for virus growth and tumor destruction and to characterize duration of caMEK expression. We also will determine feasibility of sustaining viral replication in the tumor bed by serial IR administration. Lastly, we propose to improve/optimize radio-inducibility of late viral promoters.
In Aim 2, we propose to complete analyses of malignant glioma patient databases of gene expression and clinical outcome to establish Gene Expression Profiles (GEP) that characterize radioresistance in human malignant gliomas. We identified at least three sets of genes which, when over-expressed, render tumors resistant to IR. Preliminary studies using a single glioma data base of 161 patients indicated that over-expression of any of these three gene sets correlates with a poor therapeutic response. We will use multiple databases to identify malignant glioma GEP that are associated with differential responses to therapy.
In Aim 3, we plan to study malignant glioma lines, both currently available and to be established by Project 3 Aim 1. Each tumor line will be characterized with respect to GEP. GEP patterns will then be correlated with respect to susceptibility of tumors to virus replication, radiation sensitivity and tumor destruction by combined therapy. The objective of Aim 3 is to determine whether treatment with caMEK expressing virus (R2660) + IR is effective against all malignant gliomas. We propose to identify clusters of tumors that differ with respect to gene expression and to identify over-expressed gene sets that render tumors refractory to IR and to evaluate responses of these tumors to therapeutic viruses + IR. Our goals are (i) to determine whether currently available therapeutic HSV will be effective against a broad spectrum of malignant glioma tumors, (ii) to determine whether GEPs can predict if a tumor will be refractory to treatment, and (iii) for GEP profiles that are associated with resistance to R2660 + IR, to identify novel targets to overcome in construction of improved therapeutic viruses by Project 1.
Project 2 is a component of a highly interactive Program Project Grant that is designed to improve outcome of patients with gliomas. The role of MEK will be exploited toward this end.
|Friedman, Gregory K; Bernstock, Joshua D; Chen, Dongquan et al. (2018) Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression. Sci Rep 8:13930|
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|Ring, Eric K; Li, Rong; Moore, Blake P et al. (2017) Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002. Mol Ther Oncolytics 7:27-36|
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|Friedman, Gregory K; Moore, Blake P; Nan, Li et al. (2016) Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses. Neuro Oncol 18:227-35|
|McFarland, Braden C; Marks, Margaret P; Rowse, Amber L et al. (2016) Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma. Oncotarget 7:20621-35|
|Jackson, Joshua D; Markert, James M; Li, Li et al. (2016) STAT1 and NF-?B Inhibitors Diminish Basal Interferon-Stimulated Gene Expression and Improve the Productive Infection of Oncolytic HSV in MPNST Cells. Mol Cancer Res 14:482-92|
|Friedman, Gregory K; Beierle, Elizabeth A; Gillespie, George Yancey et al. (2015) Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children. Mol Ther Oncolytics 2:|
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