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Abstract
Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [89Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (Ka) of 10−8 M−1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP+ tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP− tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers.
Highlights
Gliomas, which are brain tumors thought to originate from neurological progenitor cells, represent a diverse group of central nervous system cancers including astrocytomas, oligodendromas, ependymomas and the most aggressive, glioblastoma multiforme (GBM) [1,2,3]
Unlike other members of this protein family, fibroblast activation protein alpha (FAP) expression was observed to be negligible in normal adult tissues, but is prominently expressed on the cell surface of neuroepithelial cancer cells, on tumor associated fibroblasts in over 90% of epithelial cancers and several other pathologies [4,5,6,7,8,9]
While examining human tumor samples and tumor cells lines to understand the relevance of FAP expression, Busek and colleagues discovered elevated levels of FAP protein in most human high-grade gliomas with a mesenchymal subtype and in several glioma tumor cells lines [36,37,38,39]. Their studies indicated that FAP expression correlated with the activation of genes associated with extracellular matrix remodeling and inflammation suggesting that there may be a link between FAP expression, and the aggressive tissue remodeling, necrosis and inflammatory infiltrates observed in glioma tumors exhibiting a mesenchymal phenotype
Summary
Gliomas, which are brain tumors thought to originate from neurological progenitor cells, represent a diverse group of central nervous system cancers including astrocytomas, oligodendromas, ependymomas and the most aggressive, glioblastoma multiforme (GBM) [1,2,3]. While examining human tumor samples and tumor cells lines to understand the relevance of FAP expression, Busek and colleagues discovered elevated levels of FAP protein in most human high-grade gliomas with a mesenchymal subtype and in several glioma tumor cells lines [36,37,38,39] Their studies indicated that FAP expression correlated with the activation of genes associated with extracellular matrix remodeling and inflammation suggesting that there may be a link between FAP expression, and the aggressive tissue remodeling, necrosis and inflammatory infiltrates observed in glioma tumors exhibiting a mesenchymal phenotype. We demonstrate that the Cerenkov luminescence imaging (CLI) of FAP expression using the Cerenkov radiation, which is emitted by this radiopharmaceutical, and standard optical imaging techniques is possible [42,43,44]
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