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.
|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|
|Bolyard, Chelsea; Yoo, Ji Young; Wang, Pin-Yi et al. (2014) Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer. Clin Cancer Res 20:6479-94|
|Wojton, Jeffrey; Meisen, Walter Hans; Jacob, Naduparambil K et al. (2014) SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma. Oncotarget 5:9703-9|
|Thorne, Amy Haseley; Meisen, Walter H; Russell, Luke et al. (2014) Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance. Mol Ther 22:1678-87|
|Yoo, Ji Young; Hurwitz, Brian S; Bolyard, Chelsea et al. (2014) Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic antitumor effects. Clin Cancer Res 20:3787-98|
|Kim, Tae Hyong; Song, Jieun; Kim, Sung-Hak et al. (2014) Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells. Neuro Oncol 16:1354-64|
|Uchida, Hiroaki; Marzulli, Marco; Nakano, Kenji et al. (2013) Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther 21:561-9|
|Onishi, Manabu; Kurozumi, Kazuhiko; Ichikawa, Tomotsugu et al. (2013) Gene expression profiling of the anti-glioma effect of Cilengitide. Springerplus 2:160|
|Okemoto, Kazuo; Kasai, Kazue; Wagner, Benjamin et al. (2013) DNA demethylating agents synergize with oncolytic HSV1 against malignant gliomas. Clin Cancer Res 19:5952-9|
|Price, Richard L; Song, Jieun; Bingmer, Katherine et al. (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res 73:3441-50|
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