Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma

Kevin P Labadie; Adrienne L Lehnert; Aimee L Kenoyer; Donald K Hamlin; Andrew D Ludwig; Alan F Utria; Sara K Daniel; Tara N Mihailovic; Alexander Prossnitz; Johnnie J Orozco; Yawen Li; D Scott Wilbur; Robert S Miyaoka; James O Park

doi:10.1186/s13550-023-00980-9

Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma

EJNMMI Res. 2023 Apr 27;13(1):35. doi: 10.1186/s13550-023-00980-9.

Affiliations

¹ Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Health Sciences Bldg. Room BB-442, Box 356410, Seattle, WA, 98195-6410, USA.
² Department of Radiology, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
³ Clinical Research Division, Fred Hutch Cancer Research Center, 100 Fairview Ave N, Seattle, WA, 98109, USA.
⁴ Department of Radiation Oncology, University of Washington School of Medicine, 616 NE Northlake Pl., Seattle, WA, 98105, USA.
⁵ Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA, 98195, USA.
⁶ Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Health Sciences Bldg. Room BB-442, Box 356410, Seattle, WA, 98195-6410, USA. jopark@uw.edu.

Abstract

Background: Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (⁸⁹Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3⁺ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3⁺ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of ⁸⁹Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 μm increments. Sensitivity and specificity of PET/CT for ⁸⁹Zr-αGPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard.

Results: In tumor-bearing mice, ⁸⁹Zr-αGPC3 avidly accumulated in the tumor within four hours of injection with ongoing accumulation over time. There was minimal off-target deposition and rapid bloodstream clearance. Thirty-eight of 43 animals had an identifiable tumor on histologic analysis. ⁸⁹Zr-αGPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 μm in diameter. Tumor-to-liver ratios of ⁸⁹Zr-αGPC3 uptake were high, creating excellent spatial resolution for ease of tumor detection on PET/CT. Two of five tumors that were observed on PET/CT were not identified on histologic analysis, yielding a specificity of 60%.

Conclusions: ⁸⁹Zr-αGPC3 avidly accumulated in GPC3⁺ tumors with minimal off-target sequestration. ⁸⁹Zr-αGPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3⁺ tumors for targeted therapy. Human trials are warranted to assess its impact.

Keywords: Glypican-3 (GPC3); Hepatocellular carcinoma (HCC); Immuno-positron emission tomography (PET); Targeted molecular therapy.

Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma

Authors

Affiliations

Abstract

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