Abstract |
Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225Ac-E4G10. METHODS: We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood-brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. RESULTS: The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. CONCLUSION:
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Authors | Katja Behling, William F Maguire, Valentina Di Gialleonardo, Lukas E M Heeb, Iman F Hassan, Darren R Veach, Kayvan R Keshari, Philip H Gutin, David A Scheinberg, Michael R McDevitt |
Journal | Journal of nuclear medicine : official publication, Society of Nuclear Medicine
(J Nucl Med)
Vol. 57
Issue 11
Pg. 1771-1777
(Nov 2016)
ISSN: 1535-5667 [Electronic] United States |
PMID | 27261519
(Publication Type: Journal Article)
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Copyright | © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc. |
Chemical References |
- Antibodies, Monoclonal
- E4G10 antibody
- Dasatinib
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Topics |
- Alpha Particles
(therapeutic use)
- Animals
- Antibodies, Monoclonal
(therapeutic use)
- Blood-Brain Barrier
- Brain Neoplasms
(blood supply, pathology, radiotherapy)
- Dasatinib
(pharmacokinetics)
- Glioblastoma
(blood supply, pathology, radiotherapy)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neoplastic Stem Cells
(radiation effects)
- T-Lymphocytes, Regulatory
(immunology)
- Tumor Microenvironment
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