Imaging temozolomide-induced changes in the myeloid glioma microenvironment

Foray, Claudia; Valtorta, Silvia; Barca, Cristina; Winkeler, Alexandra; Roll, Wolfgang; Müther, Michael; Wagner, Stefan; Gardner, Miranda L.; Hermann, Sven; Schäfers, Michael; Grauer, Oliver; Moresco, Rosa María; Zinnhardt, Bastian; Jacobs, Andréas H.

doi:10.7150/thno.47269

Cited by 28 publications

(33 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In Gli36DEGFR-1 and in L0627models, sparse Iba1 signal was also present in the brain parenchyma contralateral to tumor. This data is in agreement with what recently reported by Foray et al (52). The authors found in Gli36DEGFR-1 model an increased number of peri-tumoral GAMMs and astrocytes expressing TSPO and an augmented expression of M2 phenotype myeloid markers in TMZ-treated animals.…”

Section: Discussionsupporting

confidence: 93%

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro, MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo, MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals’ survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.

show abstract

Section: Discussionsupporting

confidence: 93%

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Applying different regimens of CSF-1R inhibitor the study was divided into two parts, a preconditioning model (PM) where mice were treated with CSF-1R inhibitor 14 days prior to tumor implantation, and a repopulation model (RM) in which acute depletion and repopulation of microglial cells were performed. The mice underwent the imaging protocol of sequential gadolinium-contrast enhanced (Gd-CE) T1w-MRI, and 18F-FET-and 18F-DPA-714-PET-CT as described previously (17). Full details are available in the Supplemental M&M, Figure 1A and Figure 4A.…”

Section: Methodsmentioning

confidence: 99%

“…Imaging data were analyzed using the in-house developed software MEDgical as described previously (17). Briefly, an atlas-based right hemisphere volume-of-interest (VOI) was threshold to delineate tumor and tracer uptake volumes after co-registration of PET/CT scans with MR images.…”

Section: Volumetric Analysismentioning

confidence: 99%

Interrogating Glioma-Associated Microglia and Macrophage Dynamics Under CSF-1R Therapy with Multitracer In Vivo PET/MRI

Foray¹,

Barca²,

Winkeler

et al. 2022

J Nucl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…They believe that this model will be an important tool for drug screening and development [ 112 ]. Foray et al confirmed the efficiency of [18F] FET-PET for monitoring the TMZ-treatment response and demonstrated that in vivo TSPO-PET performed with [18F] DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME [ 113 ]. Kim et al developed a mathematical and computational model that involves reaction–diffusion equations for the important components in the tumor–microglia interaction, including the densities of tumors and microglial cells, and the concentrations of growth factors and other signaling molecules, serving as a 3-D models of the mechanical and biochemical interactions between a GBM and the tumor microenvironment.…”

Section: The Next Stepmentioning

confidence: 99%

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Chen

2021

IJMS

View full text Add to dashboard Cite

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.

show abstract

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

Cited by 28 publications

References 63 publications

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

Interrogating Glioma-Associated Microglia and Macrophage Dynamics Under CSF-1R Therapy with Multitracer In Vivo PET/MRI

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Contact Info

Product

Resources

About