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 SUV_max 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.

Acknowledgments

We thank Helena Ahtinen (Turku PET Centre, Turku University Hospital), Erica Nyman and Marja-Riitta Kajaala (Turku Centre for Disease Modeling, University of Turku), Marko Tirri (Department of Physiology, University of Turku), Minnamaija Lintunen, Sinikka Kollanus and Jaakko Liippo (Department of Pathology, Turku University Hospital) for excellent technical assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This study was conducted within the Finnish Centre of Excellence in Cardiovascular and Metabolic Diseases supported by the Academy of Finland, University of Turku, Turku University Hospital, and Åbo Akademi University. In addition, the study was financially supported by a grant from the Foundation for the Finnish Cancer Organisations. Aida Kiviniemi is a Ph.D. student supported by the National Graduate School of Clinical Investigation.