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.
|Kim, Yangjin; Yoo, Ji Young; Lee, Tae Jin et al. (2018) Complex role of NK cells in regulation of oncolytic virus-bortezomib therapy. Proc Natl Acad Sci U S A 115:4927-4932|
|Russell, Luke; Swanner, Jessica; Jaime-Ramirez, Alena Cristina et al. (2018) PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. Nat Commun 9:5006|
|Banasavadi-Siddegowda, Y K; Russell, L; Frair, E et al. (2017) PRMT5-PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurosphere cells. Oncogene 36:263-274|
|Jaime-Ramirez, Alena Cristina; Dmitrieva, Nina; Yoo, Ji Young et al. (2017) Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide. J Gene Med 19:|
|Lee, Tae Jin; Yoo, Ji Young; Shu, Dan et al. (2017) RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21. Mol Ther 25:1544-1555|
|Saini, Uksha; Naidu, Shan; ElNaggar, Adam C et al. (2017) Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target. Oncogene 36:168-181|
|Jaime-Ramirez, Alena C; Yu, Jun-Ge; Caserta, Enrico et al. (2017) Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma. Mol Ther Oncolytics 5:87-96|
|Bolyard, Chelsea; Meisen, W Hans; Banasavadi-Siddegowda, Yeshavanth et al. (2017) BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy. Clin Cancer Res 23:1809-1819|
|Quispe Calla, N E; Vicetti Miguel, R D; Boyaka, P N et al. (2016) Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection. Mucosal Immunol 9:1571-1583|
|Barth, Rolf F; Wu, Gong; Meisen, W Hans et al. (2016) Design, synthesis, and evaluation of cisplatin-containing EGFR targeting bioconjugates as potential therapeutic agents for brain tumors. Onco Targets Ther 9:2769-81|
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