Anti-angiogenic approaches that eliminate the neovasculature by inducing apoptosis would represent a significant advance in the treatment of glioblastomas. Tumor necrosis factor a (TNFa) can act to induce apoptosis of cultured primary human brain microvessel endothelial cells (MvEC) through a mechanism that requires expression of the TNF-receptor 1 (TNF-R1) on the MvEC. Immunohistochemical analysis of biopsies indicates that, in most patients, the expression of TNF-R1 and TNFa is significantly higher in the glioblastoma tumor endothelial cells as compared to the normal brain endothelial cells and the levels of tumor-associated angiogenesis in tumors developed by injection and propagation of mouse malignant glioma cells in the white matter of the mouse brain is significantly higher in TNF-R1-null mice than in their wild-type counterparts. Based on these and other data, we hypothesize that the upregulated expression of TNF-R1 on brain endothelial cells associated with malignant glioma tumors is a host anti-angiogenic response to the tumor, and that TNFa therapy targeted to tumor endothelial cells will inhibit tumor angiogenesis and tumor growth. We propose to test these hypotheses by identifying the cell surface signaling events that elicit, and regulate, TNF-R1-mediated apoptosis in glioblastoma MvECs. In parallel, we will establish the feasibility of therapeutic manipulation of TNF-R1 with a TNFa fusion protein that is targeted to tumor MvECs by fusion with a peptide that binds CD13. We will use two mouse models to analyze the specificity of the effects and the magnitude of the responses in vivo: an immune competent mouse model of glioblastoma and a xenograft model based on the use of human glioblastoma stem cells. We will: (1) Establish whether TNF-R1 is preferentially expressed in the brain tumor MvEC and is colocalized with molecules that may regulate its ability to signal apoptosis, using biopsies from patients with glioblastoma and normal brain;(2) Determine whether TNF-R1 functions as an anti-angiogenic molecule in the brain in response to a malignant glioma tumor and establish whether TNF- R2 contributes to, or modulates, this effect using TNF-R1-null, TNF1-null, and TNF-R2-null mice;(3) Determine whether the activation state or expression of integrin av?3 on the brain MvEC modulates the response of these cells to the pro-death signaling of TNF1;and (4) Test the ability of a TNFa fusion protein targeted to CD13 on tumor endothelial cells with the Cys-Asn-Gly-Arg-Cys peptide to inhibit tumor angiogenesis and tumor growth, and to promote survival, in vivo.
The results should identify a novel anti-angiogenic therapy that can be used in conjunction with other therapies to more effectively eliminate malignant glioma tumors and prevent their recurrence. The studies also will provide data concerning biomarkers that may be used to predict which glioblastoma patients may benefit from this strategy and biomarkers for non-invasive monitoring of its efficacy.
The survival of patients with glioblastoma tumors is dismal (15-18 month median survival) despite all current therapy. We propose to test a novel therapeutic strategy to preferentially kill the endothelial cells (MvECs) in the newly formed blood vessels that feed a glioblastoma tumor by targeting tumor necrosis factor a (TNFa) to these blood vessels through a peptide (NGR) that binds CD13. CD13 is upregulated on tumor endothelial cells. Importantly, we will include innovative analyses of the molecules that may regulate the responsiveness of the MvECs. This approach would be a significant advance over the therapies currently being tested that retard the growth of the blood vessels, but do not eliminate them.
|Ahluwalia, Manmeet S; Bou-Anak, Stephanie; Burgett, Monica E et al. (2017) Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma. J Neurooncol 131:449-458|
|Burgett, Monica E; Lathia, Justin D; Roth, Patrick et al. (2016) Direct contact with perivascular tumor cells enhances integrin ?v?3 signaling and migration of endothelial cells. Oncotarget 7:43852-43867|
|Hale, James S; Otvos, Balint; Sinyuk, Maksim et al. (2014) Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression. Stem Cells 32:1746-58|
|Grove, Lisa M; Southern, Brian D; Jin, Tong H et al. (2014) Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts. J Biol Chem 289:12791-804|
|Liu, Wei Michael; Huang, Ping; Kar, Niladri et al. (2013) Lyn facilitates glioblastoma cell survival under conditions of nutrient deprivation by promoting autophagy. PLoS One 8:e70804|
|Ding, Qiang; Cai, Guo-Qiang; Hu, Meng et al. (2013) FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis. Am J Pathol 182:1572-84|
|Huang, Ping; Rani, M R Sandhya; Ahluwalia, Manmeet S et al. (2012) Endothelial expression of TNF receptor-1 generates a proapoptotic signal inhibited by integrin *6*1 in glioblastoma. Cancer Res 72:1428-37|
|Lathia, Justin D; Li, Meizhang; Hall, Peter E et al. (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72:766-78|
|Cai, Guo-qiang; Zheng, Anni; Tang, Qingjiu et al. (2010) Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts. Exp Cell Res 316:1600-9|
|Gladson, Candece L; Prayson, Richard A; Liu, Wei Michael (2010) The pathobiology of glioma tumors. Annu Rev Pathol 5:33-50|
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