Feasibility of experimental BT4C glioma models for somatostatin receptor 2-targeted therapies

Abstract

Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas.Methods. Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [68Ga]DOTA-(Tyr3)-Octreotide ([68Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[18F]fluororibose-NOC ([18F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression.Results. Increased tumor uptake of [68Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [68Ga]DOTATOC and [18F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [68Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [68Ga]DOTATOC or [18F]FDR-NOC PET.Conclusions. Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [68Ga]DOTATOC or [18F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr2 status.