Because of hypervascular nature of glioblastoma (GBM) and associated active angiogenesis, investigators have added anti-angiogenic treatment as an adjuvant to normalize blood vessels and control abnormal angiogenesis. Antiangiogenic therapy disturbs tumor vasculature, leading to marked hypoxia. In GBM, hypoxia leads to up-regulation of hypoxia inducible factor 1-alpha (HIF-1). HIF-1 up-regulates SDF-1, which in turn may recruit various pro-angiogenic bone marrow-derived cells. Any therapy that invites more EPCs might promote neovascularization and pro growth, a paradoxical effect of anti-angiogenic therapy. Therefore, we hypothesize that anti-angiogenic treatment using VEGFR inhibitors would initiate the release of pro-angiogenic factors, causing migration and accumulation of endothelial progenitor cells (EPCs) or bone marrow progenitor cells (BMPCs) (different types of stem cells), and enhanced angiogenesis in refractory tumors. The goal of this study is to elucidate neovascularization mechanisms in refractory glioma by making chimeric mouse model and applying novel non-invasive, state of the art MRI and optical imaging approach to monitor tumor progression and associated exogenous and endogenous EPCs'migration. We will conduct the research in three phases: (1) we will establish chimeric mouse model where bone marrow of sub-lethally irradiated athymic mouse will be replaced by bone marrow cells collected from bone marrow of transgenic mouse (C57BL/6-Tg(UBC-GFP)30Scha/J) that express GFP protein under the control of human ubiquitin C promoter. These chimeric mice will be used to generate orthotopic human glioma. (2) we'll determine the changes in tumor vascular permeability, enhancement patterns, distribution volume, and diffusion parameters by MRI, and changes in different angiogenic factors and their associated receptors in the tumor and surrounding tissues following the treatment with vetanalib or AMD3100 (or a newer potent CXCR4 inhibitor), separately or in combination;(3) we'll determine the involvement of endogenous BMPCs and exogenous EPCs by optical imaging and cellular MRI, respectively, during antiangiogenic treatments with vetanalib or AMD3100 (or a newer potent CXCR4 inhibitor), separately or in combination, and the findings will be correlated with the expression o angiogenic factors and receptors. Involvement of endogenous BMPCs and exogenous EPCs in tumor neovascularization will also be compared and correlated. It is anticipated that there is a strong role of stem cells during anti-angiogenic therapy. Differences in accumulation of the endogenous or administered stem cells following different treatment schedule will prove our hypothesis that there is a role for stem cells during anti-angiogenic treatment. Correlation of the accumulated administered stem cells with MRI findings and the expression of different angiogenic receptors will help clinicians to modify treatment strategy when anti-angiogenic therapy is considered.

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The proposed investigations will shed new lights on the mechanisms of tumor neovascularization following anti-angiogenic/anti-vasculogenic treatments and apply both optical and MR imaging techniques to track changes in the tumor. Specifically: 1) we'll create a chimeric animal model by replacing bone marrow cells with GFP+ bone marrow, 2) we will use established imaging modalities and techniques to determine, in vivo, the changes in the tumors during anti-angiogenic/anti-vasculogenic treatments, 3) by optical imaging we'll track the migration of endogenous GFP+ bone marrow progenitor cells to the sites of tumor, 4) we will use exogenous stem cells to determine the role of stem cells during anti-angiogenic/anti-vasculogenic treatments by MRI, 5) we will use both optical imaging and cellular MRI to track how progenitor cells become involved in tumor angiogenesis/vasculogenesis during anti-angiogenic/anti-vasculogenic treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DTCS-A (81))
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Henderson, Lori A
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Henry Ford Health System
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Angara, Kartik; Rashid, Mohammad H; Shankar, Adarsh et al. (2016) Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies. Histol Histopathol :11856
Achyut, B R; Shankar, Adarsh; Iskander, A S M et al. (2016) Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments. Cancer Biol Ther 17:280-90
Shaaban, S; Alsulami, M; Arbab, S A et al. (2016) Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. Int J Cancer Res 12:69-81
Achyut, Bhagelu R; Arbab, Ali S (2016) Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther 9:1047-55
Shankar, Adarsh; Borin, Thaiz F; Iskander, Asm et al. (2016) Combination of vatalanib and a 20-HETE synthesis inhibitor results in decreased tumor growth in an animal model of human glioma. Onco Targets Ther 9:1205-19
Achyut, B R; Shankar, Adarsh; Iskander, A S M et al. (2015) Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. Cancer Lett 369:416-26
Arbab, Ali S; Jain, Meenu; Achyut, B R (2015) Vascular Mimicry: The Next Big Glioblastoma Target. Biochem Physiol 4:
Jain, Meenu; Arbab, Ali S; Achyut, B R (2015) When Seed and Soil Theory Meets Chicken or Egg Theory in Cancer Metastasis. Biochem Physiol 4:
Borin, Thaiz Ferraz; Zuccari, Debora A P C; Jardim-Perassi, Bruna V et al. (2014) HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice. PLoS One 9:e116247
Achyut, B R; Arbab, Ali S (2014) Myeloid Derived Suppressor Cells: Fuel the Fire. Biochem Physiol 3:e123

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