Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles.
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 with225Ac-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 by225Ac-E4G10.


METHODS
We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of225Ac-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.


CONCLUSIONS
Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor-driven glioblastoma.
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Katja
K
Behling
Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
William F
WF
Maguire
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Valentina
V
Di Gialleonardo
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Lukas E M
LE
Heeb
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Iman F
IF
Hassan
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Darren R
DR
Veach
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Kayvan R
KR
Keshari
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
Philip H
PH
Gutin
Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pharmacology, Weill Cornell Medical College, New York, New York; and.
David A
DA
Scheinberg
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York m-mcdevitt@ski.mskcc.org.|Department of Medicine, Weill Cornell Medical College, New York, New York.
Michael R
MR
McDevitt
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D000069439:Dasatinib / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000528:radiation effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059016:Tumor Microenvironment
D000911:Antibodies, Monoclonal; C550191:E4G10 antibody; D000069439:Dasatinib
225Ac; actinium-225; glioblastoma; pericytes; radioimmunotherapy; vascular endothelium