PSMA PET Imaging in Glioblastoma: A Preclinical Evaluation and Theranostic Outlook

Abstract

BackgroundProstate specific membrane antigen (PSMA) PET imaging has recently gained attention in glioblastoma (GBM) patients as a potential theranostic target for PSMA radioligand therapy. However, PSMA PET has not yet been established in a murine GBM model. Our goal was to investigate the potential of PSMA PET imaging in the syngeneic GL261 GBM model and to give an outlook regarding the potential of PMSA radioligand therapy in this model.MethodsWe performed an 18F-PSMA-1007 PET study in the orthotopic GL261 model (n=14 GBM, n=7 sham-operated mice) with imaging at day 4, 8, 11, 15, 18 and 22 post implantation. Time-activity-curves (TAC) were extracted from dynamic PET scans (0-120 min p. i.) in a subset of mice (n=4 GBM, n=3 sham-operated mice) to identify the optimal time frame for image analysis, and standardized-uptake-values (SUV) as well as tumor-to-background ratios (TBR) using contralateral normal brain as background were calculated in all mice. Additionally, computed tomography (CT), ex vivo and in vitro18F-PSMA-1007 autoradiographies (ARG) were performed.ResultsTAC analysis of GBM mice revealed a plateau of TBR values after 40 min p. i. Therefore, a 30 min time frame between 40-70 min p. i. was chosen for PET quantification. At day 15 and later, GBM mice showed a discernible PSMA PET signal on the inoculation site, with highest TBRmean in GBM mice at day 18 (7.3 ± 1.3 vs. 1.6 ± 0.3 in shams; p=0.024). Ex vivo ARG confirmed high tracer signal in GBM compared to healthy background (TBRmean 26.9 ± 10.5 vs. 1.6 ± 0.7 in shams at day 18/22 post implantation; p=0.002). However, absolute uptake values in the GL261 tumor remained low (e.g., SUVmean 0.21 ± 0.04 g/ml at day 18) resulting in low ratios compared to dose-relevant organs (e.g., mean tumor-to-kidney ratio 1.5E-2 ± 0.5E-2).ConclusionsAlthough 18F-PSMA-1007 PET imaging of GL261 tumor-bearing mice is feasible and resulted in high TBRs, absolute tumoral uptake values remained low and hint to limited applicability of the GL261 model for PSMA-directed therapy studies. Further investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in GBM.

Discriminating Inflammatory Radiation-Related Changes From Early Recurrence in Patients With Glioblastomas

“…However, the definition of a “significant uptake” remains undefined. In a preclinical study, Kirchner et al 56 confirmed a high TBR due to low expression in normal brain parenchyma, but a low absolute tumoral uptake. Similarly, some authors have highlighted that PSMA-based targeted therapy could be restricted because of a low target-to-liver ratio.…”

Diagnostic Accuracy of PET/CT or PET/MRI Using PSMA-Targeting Radiopharmaceuticals in High-Grade Gliomas: A Systematic Review and a Bivariate Meta-Analysis

“…Some case reports demonstrated promising results for the implementation of PSMA-targeted therapy in HGG [ 32 , 33 ]. A preclinical study has recently demonstrated that although PSMA-targeted PET in a specific murine model of glioblastoma is feasible and resulted in high TBR, absolute tumoral uptake values remained low limiting the applicability of this murine model for PSMA-targeted therapy [ 34 ]. Overall, further preclinical investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in HGG, and further clinical studies using PSMA-targeted agents radiolabelled with alpha- or beta-emitting radionuclides are needed to confirm the value of PSMA-targeted theranostics in HGG.…”

PSMA Avidity in the Heterotropic Ossification—An Incidental Finding on PSMA PET/CT

“…PSMA avidity is detected in various nonprostatic benign and malignant conditions. 1,2 HO is a diverse pathologic process, characterized by formation of extraskeletal bone in any connective tissue such as the skeletal muscles, fascia, tendon, ligament, subcutis, skin, vascular wall, and so on. 3 The new bone formation in HO is associated with the inflammatory process and neovascularization, which are believed to contribute for PSMA uptake in HO.…”

“…This case demonstrates the incidental detected PSMA avidity in the HO. PSMA avidity is detected in various nonprostatic benign and malignant conditions 1,2 . HO is a diverse pathologic process, characterized by formation of extraskeletal bone in any connective tissue such as the skeletal muscles, fascia, tendon, ligament, subcutis, skin, vascular wall, and so on 3 .…”