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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA071933-15
Application #
8504706
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$232,718
Indirect Cost
$35,576
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Friedman, G K; Nan, L; Haas, M C et al. (2015) ??34.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia. Gene Ther 22:348-55
Jackson, J D; McMorris, A M; Roth, J C et al. (2014) Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines. Gene Ther 21:984-90
Cody, James J; Markert, James M; Hurst, Douglas R (2014) Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells. PLoS One 9:e92919
Roth, Justin C; Cassady, Kevin A; Cody, James J et al. (2014) Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev 25:16-27
Widau, Ryan C; Parekh, Akash D; Ranck, Mark C et al. (2014) RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation. Proc Natl Acad Sci U S A 111:E484-91
Smith, Tyrel T; Roth, Justin C; Friedman, Gregory K et al. (2014) Oncolytic viral therapy: targeting cancer stem cells. Oncolytic Virother 2014:21-33
Markert, James M; Razdan, Shantanu N; Kuo, Hui-Chien et al. (2014) A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 22:1048-55
Pressey, Joseph G; Haas, Marilyn C; Pressey, Christine S et al. (2013) CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV. Pediatr Blood Cancer 60:45-52
Liauw, Stanley L; Connell, Philip P; Weichselbaum, Ralph R (2013) New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med 5:173sr2
Gillory, Lauren A; Megison, Michael L; Stewart, Jerry E et al. (2013) Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma. PLoS One 8:e77753

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