High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

Oliveira, Dennis; Stegmayr, Carina; Heinzel, Alexander; Neumaier, Bernd; Shah, N. Jon; Mottaghy, Felix M.; Langen, Karl‐Josef; Willuweit, Antje

doi:10.1186/s13550-020-00642-0

Cited by 15 publications

(11 citation statements)

References 35 publications

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“…Interestingly, high resolution ex vivo ARG showed a slightly increased uptake in the tumor periphery, which has been previously described in a GBM model in rats by Oliveira et al. (2020) ( 32 ). The authors relate this enhanced uptake in the tumor periphery to astrocytic activation, which has yet to be confirmed for the GL261 model.…”

Section: Discussionsupporting

confidence: 77%

“…Further, circumventricular organs which dispose of highly permeable capillaries showed high 18 F-PSMA-1007 tracer accumulation in ex vivo ARG as well ( Figure 2F ), which is probably related to the absence of a BBB in this area. Thus, the increased PET signal in GBM might be analogously related to unspecific tracer accumulation in areas with disrupted BBB, although an additional specific uptake component cannot be excluded, as previously shown ( 32 ). Likewise, unspecific 18 F-PSMA-1007 signal caused by a BBB defect has been reported before by Salas Fragomeni et al.…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 63%

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

et al. 2021

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“…According to previous immunohistochemical studies on PSMA expression in glioblastoma, the non-endothelial PSMA staining seems to be primarily related to tumor cells ( 12 ). Interestingly, preclinical and clinical data reveal PSMA radioligand uptake in activated astrocytes as well, which might confound the evaluation of PSMA uptake in non-endothelial tumor cells ( 38 , 39 ). However, a reliable differentiation between tumor cells and stationary astrocytes in IDH -wildtype gliomas is not yet feasible using immunohistochemical methods, as there is still no marker that clearly distinguishes between both.…”

Section: Discussionmentioning

confidence: 99%

PSMA Expression in Glioblastoma as a Basis for Theranostic Approaches: A Retrospective, Correlational Panel Study Including Immunohistochemistry, Clinical Parameters and PET Imaging

et al. 2021

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AimThe aim of the current study was to enlighten the evolution of prostate-specific membrane antigen (PSMA) expression in glioblastoma between initial diagnosis and recurrence in order to provide preliminary insight for further clinical investigations into innovative PSMA-directed treatment concepts in neuro-oncology.MethodsPatients who underwent resection for de-novo glioblastoma (GBM) and had a re-resection in case of a recurrent tumor following radiochemotherapy and subsequent chemotherapy were included (n = 16). Histological and immunohistochemical stainings were performed at initial diagnosis and at recurrence (n = 96 tissue specimens). Levels of PSMA expression both in endothelial and non-endothelial cells as well as vascular density (CD34) were quantified via immunohistochemistry and changes between initial diagnosis and recurrence were determined. Immunohistochemical findings were correlated with survival and established clinical parameters.ResultsPSMA expression was found to be present in all GBM tissue samples at initial diagnosis as well as in all but one case of recurrent tumor samples. The level of PSMA expression in glioblastoma varied inter-individually both in endothelial and non-endothelial cells. Likewise, the temporal evolution of PSMA expression highly varied in between patients. The level of vascular PSMA expression at recurrence and its change between initial diagnosis and recurrence was associated with post recurrence survival time: Patients with high vascular PSMA expression at recurrence as well as patients with increasing PSMA expression throughout the disease course survived shorter than patients with low vascular PSMA expression or decreasing vascular PSMA expression. There was no significant correlation of PSMA expression with MGMT promoter methylation status or Ki-67 labelling index.ConclusionPSMA is expressed in glioblastoma both at initial diagnosis and at recurrence. High vascular PSMA expression at recurrence seems to be a negative prognostic marker. Thus, PSMA expression in GBM might present a promising target for theranostic approaches in recurrent glioblastoma. Especially PSMA PET imaging and PSMA-directed radioligand therapy warrant further studies in brain tumor patients.

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“…Very few astrocytes were noted in the centre of the tumours. These data suggest that PSMA radioligand could also visualize astrocytes activation [266].…”

Section: Other Targets Of Tumour Microenvironmentmentioning

confidence: 75%

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

Valtorta

Salvatore

Rainone

et al. 2020

IJMS

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This review highlights the importance and the complexity of tumour biology and microenvironment in the progression and therapy resistance of glioma. Specific gene mutations, the possible functions of several non-coding microRNAs and the intra-tumour and inter-tumour heterogeneity of cell types contribute to limit the efficacy of the actual therapeutic options. In this scenario, identification of molecular biomarkers of response and the use of multimodal in vivo imaging and in particular the Positron Emission Tomography (PET) based molecular approach, can help identifying glioma features and the modifications occurring during therapy at a regional level. Indeed, a better understanding of tumor heterogeneity and the development of diagnostic procedures can favor the identification of a cluster of patients for personalized medicine in order to improve the survival and their quality of life.

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High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

Cited by 15 publications

References 35 publications

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

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

PSMA Expression in Glioblastoma as a Basis for Theranostic Approaches: A Retrospective, Correlational Panel Study Including Immunohistochemistry, Clinical Parameters and PET Imaging

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

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