Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR
Spencer C. Behr, … , Susan M. Chang, Michael J. Evans
Spencer C. Behr, … , Susan M. Chang, Michael J. Evans
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e93999. https://doi.org/10.1172/jci.insight.93999.
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Categories: Clinical Medicine Neuroscience Oncology

Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR

Abstract

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor–dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7–10.2 mCi 68Ga-citrate and were imaged with PET/MR 123–307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

Authors

Spencer C. Behr, Javier E. Villanueva-Meyer, Yan Li, Yung-Hua Wang, Junnian Wei, Anna Moroz, Julia K.L. Lee, Jeffrey C. Hsiao, Kenneth T. Gao, Wendy Ma, Soonmee Cha, David M. Wilson, Youngho Seo, Sarah J. Nelson, Susan M. Chang, Michael J. Evans

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Figure 1

Preclinical data showing that 68Ga-citrate uptake is TFRC dependent in glioblastoma tumors in vivo.

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Preclinical data showing that 68Ga-citrate uptake is TFRC dependent in g...
(A) A biodistribution study showing the accumulation of 68Ga-citrate in normal mouse tissues and subcutaneous U87 MG tumors at 2, 4, and 6 hours after injection. Tumor-bearing nu/nu mice (n = 6/time point) received ~400 μCi 68Ga-citrate via tail vein. Peak radiotracer uptake was observed in the tumors at 4 hours after injection. The data were reproduced in 2 independent animal cohorts, and the cumulative data are represented in the figure. (B) Ex vivo biodistribution data from selected tissues showing the effect on 68Ga-citrate biodistribution due to co-administration of an anti-TFRC antibody that disrupts the interaction between Tf and TFRC. Intact male nu/nu mice bearing subcutaneous U87 MG tumors (n = 4–7/treatment arm) received 68Ga-citrate (~400 μCi/mouse) or 68Ga-citrate (~400 μCi/mouse) 24 hours after administration of 100 μg DF1535, a monoclonal antibody (IgG) that binds an extracellular epitope on TFRC and disrupts Tf uptake into cells in vitro. The biodistribution data were collected 4 hours after injection of 68Ga-citrate. Approximately 50% of the 68Ga-citrate accumulation in the tumors was suppressed by DF1513 (#P < 0.01), underscoring that 68Ga-citrate localizes to tumors by binding Tf in situ. Moreover, radiotracer accumulation was higher in the blood pool of mice treated with DF1513, consistent with a model in which 68Ga-citrate exists in the blood bound to a large biomolecule (MW of Tf, ~80 kDa). Last, radiotracer uptake was competed with DF1513 in the bone (*P < 0.01). Overall, these data show that 68Ga accumulates in tumors within 4 hours after injection in a TFRC-dependent fashion. Statistically significant differences were calculated using an unpaired, 2-tailed Student’s t test. The data were reproduced in an additional animal cohort. Horizontal lines are placed to bridge the treatment arms for which a Student’s t test was applied to determine statistical significance.