학술논문
Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma
Original Research
Original Research
Document Type
Academic Journal
Author
Source
EJNMMI Research. December 2023, Vol. 13 Issue 1
Subject
Language
English
Abstract
Author(s): Kevin P. Labadie [sup.1], Adrienne L. Lehnert [sup.2], Aimee L. Kenoyer [sup.3], Donald K. Hamlin [sup.4], Andrew D. Ludwig [sup.1], Alan F. Utria [sup.1], Sara K. Daniel [sup.1], Tara [...]
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 (.sup.89Zr-[alpha]GPC3) for use in positron emission tomography (PET) for detection of small, GPC3.sup.+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3.sup.+ 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 .sup.89Zr-[alpha]GPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 [mu]m increments. Sensitivity and specificity of PET/CT for .sup.89Zr-[alpha]GPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard. Results In tumor-bearing mice, .sup.89Zr-[alpha]GPC3 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. .sup.89Zr-[alpha]GPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 [mu]m in diameter. Tumor-to-liver ratios of .sup.89Zr-[alpha]GPC3 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 .sup.89Zr-[alpha]GPC3 avidly accumulated in GPC3.sup.+ tumors with minimal off-target sequestration. .sup.89Zr-[alpha]GPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3.sup.+ tumors for targeted therapy. Human trials are warranted to assess its impact.
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 (.sup.89Zr-[alpha]GPC3) for use in positron emission tomography (PET) for detection of small, GPC3.sup.+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3.sup.+ 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 .sup.89Zr-[alpha]GPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 [mu]m increments. Sensitivity and specificity of PET/CT for .sup.89Zr-[alpha]GPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard. Results In tumor-bearing mice, .sup.89Zr-[alpha]GPC3 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. .sup.89Zr-[alpha]GPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 [mu]m in diameter. Tumor-to-liver ratios of .sup.89Zr-[alpha]GPC3 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 .sup.89Zr-[alpha]GPC3 avidly accumulated in GPC3.sup.+ tumors with minimal off-target sequestration. .sup.89Zr-[alpha]GPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3.sup.+ tumors for targeted therapy. Human trials are warranted to assess its impact.