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Multimodality Molecular Imaging of Glioblastoma Growth Inhibition with Vasculature-Targeting Fusion Toxin VEGF₁₂₁/rGel

¹ The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California; ² Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; ³ Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas; and ⁴ Department of Pathology, Stanford University School of Medicine, Stanford, California

Correspondence: For correspondence or reprints contact: Xiaoyuan (Shawn) Chen, PhD, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd., P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF₁₂₁/rGel) composed of the VEGF-A isoform VEGF₁₂₁ linked with a G₄S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET. Methods: Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with ⁶⁴Cu-1,4,7,10-tetraazacyclododedane-N,N',N'',N'''-tetraacetic acid (DOTA)-VEGF₁₂₁/rGel was performed before VEGF₁₂₁/rGel treatment. ¹⁸F-Fluorothymidine (¹⁸F-FLT) scans were obtained before and after treatment to evaluate VEGF₁₂₁/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. Results: Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with ⁶⁴Cu-DOTA-VEGF₁₂₁/rGel before treatment revealed a tumor accumulation (mean ± SD) of 11.8 ± 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF₁₂₁. PET with ¹⁸F-FLT revealed significant a decrease in tumor proliferation in VEGF₁₂₁/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF₁₂₁/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. Conclusion: The results of this study suggest that future clinical multimodality imaging and therapy with VEGF₁₂₁/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF₁₂₁/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.

Key Words: glioblastoma multiforme • VEGFR-2 (Flk-1/KDR) • gelonin • VEGF₁₂₁ • angiogenesis

^* Contributed equally to this work.

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