The ultimate goal of this proposal is to understand the contribution of Vstat120 expressing oncolytic viruses on OV propagation, tumor biology and anti-tumor efficacy. These results will lead to a better understanding of OV therapy induced changes in tumor biology and will lead to the development of a dually armed cancer killing OV. The OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from six clinical trials using replication competent OVs to treat patients with malignant glioma 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. My laboratory has recently created two oncolytic viruses, armed with an anti-angiogenic gene. We now propose to elucidate the role of this angiostatic protein in viral propagation, glioma biology and OV efficacy.
The American Cancer Society predicts that there will be 12,740 deaths due to cancers of the brain/nervous system. Despite decades of research prognosis for patients suffering from malignant gliomas remains poor. Oncolytic viral therapy is an experimental treatment which is currently being evaluated in clinical trials for efficacy against brain tumors. The proposed research outlined in this grant is highly significant because it will elucidate the impact of an oncolytic virus armed with Vstat120 on tumor microenvironment, and OV efficacy. The results will help translate oncolytic viral therapy into an efficacious treatment for tumors.
|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|
|Stephenson, Jason R; Paavola, Kevin J; Schaefer, Stacy A et al. (2013) Brain-specific angiogenesis inhibitor-1 signaling, regulation, and enrichment in the postsynaptic density. J Biol Chem 288:22248-56|
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