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).
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.
|Yoo, Ji Young; Jaime-Ramirez, Alena Cristina; Bolyard, Chelsea et al. (2016) Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy. Clin Cancer Res 22:5265-5276|
|Ru, Peng; Hu, Peng; Geng, Feng et al. (2016) Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth. Cell Rep 16:1527-35|
|Cheng, Chunming; Ru, Peng; Geng, Feng et al. (2015) Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth. Cancer Cell 28:569-81|
|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|
|Han, Jianfeng; Chen, Xilin; Chu, Jianhong et al. (2015) TGFÎ² Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response. Cancer Res 75:5273-82|
|Yoo, Ji Young; Yu, Jun-Ge; Kaka, Azeem et al. (2015) ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma. Mol Ther Oncolytics 2:15008|
|Meisen, W Hans; Wohleb, Eric S; Jaime-Ramirez, Alena Cristina et al. (2015) The Impact of Macrophage- and Microglia-Secreted TNFÎ± on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment. Clin Cancer Res 21:3274-85|
|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|
|Jacobsen, Karly; Russell, Luke; Kaur, Balveen et al. (2015) Effects of CCN1 and Macrophage Content on Glioma Virotherapy: A Mathematical Model. Bull Math Biol 77:984-1012|
|Lee, Tae Jin; Haque, Farzin; Shu, Dan et al. (2015) RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model. Oncotarget 6:14766-76|
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