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Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening
Published on: September 5, 2025
Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in
Cheng Miao1,2, Zehua Ding3, Jiaxing Wu3
1Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongi University, Shanghai, China. miaocheng95@foxmail.com.
Abstract:
The standard care of glioblastomas (GBM) confers limited survival benefit for patients due to the rapid tumor recurrence. Targeting tumor-associated macrophages/microglia via colony-stimulating factor 1 receptor (CSF-1R) inhibition is potentially effective in suppressing GBM recurrence. However, clinical trials of CSF-1R inhibitors failed to achieve their goal due to GBM resistance to anti-CSF-1R therapy. Here, we identified and verified key resistance mechanisms of anti-CSF-1R therapy by translatome profiling-combined analyses. To solve above problem, we have established a highly stable and refractory mouse G422TN-GBM model, in which temozolomide (TMZ) is the most effective monotherapy but can only slightly extend animal survival. To identify effective resistance mechanism of anti-CSF1R therapy in GBM, we first apply the Translating ribosome affinity purification (TRAP) RNA-sequencing techniques in GBM tissues, which have previously used in neuroscience. TRAP-seq identified oxidative phosphorylation/glycolysis as anti-CSF1R therapy resistance mechanism, and it's combined with Cancer Therapeutics Response Portal (CTRP) identified piperlongumine (PL) or vorinostat (SAHA) as targeting drugs. PL or SAHA enhanced PLX3397 efficacy by reversing oxidative phosphorylation/glycolysis dysregulation in vitro and in vivo. The triple combination of PLX3397, TMZ, and PL/SAHA significantly improved survival in G422TN-GBM mice. In conclusion, targeting oxidative phosphorylation/glycolysis by PL or SAHA prominently improves therapeutic efficacy of PLX3397 + TMZ in GBM, which deserves priority for clinical trials. Our study also reveals that translatome profiling is efficient for uncovering drug-resistant targets.
Insights
Targeting colony-stimulating factor 1 receptor (CSF-1R) resistance in glioblastoma (GBM) requires addressing oxidative phosphorylation/glycolysis. Combining piperlongumine (PL) or vorinostat (SAHA) with CSF-1R inhibitors and temozolomide (TMZ) significantly improves GBM survival in mice.
Area of Science:
- Neuro-oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Standard glioblastoma (GBM) care offers limited survival benefits due to rapid tumor recurrence.
- Colony-stimulating factor 1 receptor (CSF-1R) inhibition shows promise for suppressing GBM recurrence but faces clinical resistance.
- Existing clinical trials of CSF-1R inhibitors have been unsuccessful due to GBM's resistance to anti-CSF-1R therapy.
Purpose of the Study:
- To identify and verify key mechanisms of resistance to anti-CSF-1R therapy in glioblastoma.
- To establish a refractory mouse GBM model for studying therapeutic resistance.
- To discover novel therapeutic strategies to overcome anti-CSF-1R therapy resistance in GBM.
Main Methods:
- Utilized a stable and refractory mouse G422TN-GBM model.
- Employed Translating Ribosome Affinity Purification (TRAP) RNA-sequencing to profile GBM tissues.
- Integrated Cancer Therapeutics Response Portal (CTRP) data to identify potential targeting drugs.
Main Results:
- TRAP-seq identified oxidative phosphorylation/glycolysis as a key resistance mechanism to anti-CSF-1R therapy.
- Piperlongumine (PL) or vorinostat (SAHA) were identified as drugs targeting this resistance pathway.
- The combination of PL/SAHA with PLX3397 (CSF-1R inhibitor) reversed metabolic dysregulation and enhanced efficacy in vitro and in vivo.
- A triple combination of PLX3397, temozolomide (TMZ), and PL/SAHA significantly improved survival in the G422TN-GBM mouse model.
Conclusions:
- Targeting oxidative phosphorylation/glycolysis with PL or SAHA enhances the therapeutic efficacy of PLX3397 + TMZ in GBM.
- This combination therapy warrants priority for clinical trials in glioblastoma patients.
- Translatome profiling is an effective method for uncovering drug-resistant targets in cancer.
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