The ultimate goal of this proposal is to evaluate the changes induced in the tumor microenvironment upon treatment with oncolytic viruses (OV) and assess how these changes impact OV therapy. These results will lead to a better understanding of OV therapy induced changes in tumor biology. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent no- neoplastic tissue. Results from clinical trials using replication competent OVs to treat patients with malignant gliomas have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. We are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. In our preliminary studies, we have uncovered a significant increase in the release of HMGB1. HMGB1 is normally a cellular protein which is released into the extracellular environment upon certain stimuli and can serve as a damage associated molecular pattern. In this study we will evaluate the impact of this extracellular HMGB1 on tumor microenvironment, its impact on endothelial cells (Aim 1), macrophages (Aim 2) and antigen presentation to T cells (Aim 3).

Public Health Relevance

According the NCI there will be estimated 23,130 new diagnosed cases of CNS tumors in 2013, and an estimated 14,080 predicted deaths from these tumors in 2013. Glioblastoma (GB), a grade IV malignant brain tumor, is the most common adult primary brain tumor and despite recent advances in understanding molecular analysis of these tumors, prognosis for patients affected with this disease is less than 15 months. Thus there is an urgent and unmet need to advance novel therapeutics for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS064607-06
Application #
8720410
Study Section
Special Emphasis Panel (ZRG1-OTC-Y (02))
Program Officer
Fountain, Jane W
Project Start
2008-08-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$336,602
Indirect Cost
$117,852
Name
Ohio State University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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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
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