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Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models
Sourav Bhaduri1, Claire Louise Kelly1, Clémentine Lesbats1,2
1Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Abstract:
Changes in glioblastoma (GBM) metabolism was investigated in response to JAS239, a choline kinase inhibitor, using MRS. In addition to the inhibition of phosphocholine synthesis, we investigated changes in other key metabolic pathways associated with GBM progression and treatment response. Three syngeneic rodent models of GBM were used: F98 (N = 12) and 9L (N = 8) models in rats and GL261 (N = 10) in mice. Rodents were intracranially injected with GBM cells in the right cortex and tumor growth was monitored using T2 -weighted images. Animals were treated once daily with intraperitoneal injections of 4 mg/kg JAS239 (F98 rats, n = 6; 9L rats, n = 6; GL261 mice, n = 5) or saline (control group, F98 rats, n = 6; 9L rats, n = 2; GL261 mice, n = 5) for five consecutive days. Single voxel spectra were acquired on Days 0 (T0, baseline) and 6 (T6, end of treatment) from the tumor as well as the contralateral normal brain using a PRESS sequence. Changes in metabolite ratios (tCho/tCr, tCho/NAA, mI/tCr, Glx/tCr and (Lip + Lac)/Cr) were used to assess metabolic pathway alterations in response to JAS239. Tumor growth arrest was noted in all models in response to JAS239 treatment compared with saline-treated animals, with a significant reduction (p < 0.05) in the F98 model. A reduction in tCho/tCr was observed with JAS239 treatment in all GBM models, indicating reduced phospholipid metabolism, with the highest reduction in 9L followed by GL261 and F98 tumors. A significant reduction (p < 0.05) in the tCho/NAA ratio was observed in the 9L model. A significant reduction in mI/tCr (p < 0.05) was found in JAS239-treated F98 tumors compared with the saline-treated animals. A non-significant trend of reduction in Glx/tCr was observed only in F98 and 9L tumors. JAS239-treated F98 tumors also showed a significant increase in Lip + Lac (p < 0.05), indicating increased cell death. This study demonstrated the utility of MRS in assessing metabolic changes in GBM in response to choline kinase inhibition.
Insights
JAS239, a choline kinase inhibitor, demonstrated tumor growth arrest in glioblastoma (GBM) models. Magnetic Resonance Spectroscopy (MRS) revealed reduced phospholipid metabolism and increased cell death, showcasing MRS utility in assessing GBM metabolic changes.
Area of Science:
- Oncology
- Biochemistry
- Medical Imaging
Background:
- Glioblastoma (GBM) exhibits altered metabolism, presenting therapeutic challenges.
- Choline kinase (ChoK) is a key enzyme in phospholipid metabolism, implicated in GBM progression.
- Targeting GBM metabolism offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate metabolic changes in GBM in response to JAS239, a choline kinase inhibitor, using Magnetic Resonance Spectroscopy (MRS).
- To assess the impact of JAS239 on key metabolic pathways beyond phosphocholine synthesis in GBM.
- To evaluate the utility of MRS in monitoring GBM response to targeted metabolic therapy.
Main Methods:
- Three syngeneic rodent GBM models (F98, 9L, GL261) were used.
- Animals were treated with JAS239 or saline, and tumor growth was monitored.
- Proton Magnetic Resonance Spectroscopy (MRS) was employed to acquire single voxel spectra from tumors and contralateral brain before and after treatment.
Main Results:
- JAS239 treatment resulted in tumor growth arrest across all models.
- A significant reduction in the total choline to creatine ratio (tCho/tCr) was observed in all JAS239-treated GBM models, indicating decreased phospholipid metabolism.
- Specific metabolic alterations included reduced tCho/NAA in 9L, reduced myo-inositol to creatine ratio (mI/tCr) in F98, and increased (Lipids + Lactate) to Creatine ratio ((Lip+Lac)/Cr) in F98, suggesting increased cell death.
Conclusions:
- JAS239 effectively inhibits choline kinase, leading to metabolic perturbations and growth arrest in GBM models.
- MRS is a valuable tool for non-invasively assessing metabolic pathway alterations and treatment response in GBM.
- Targeting choline metabolism with inhibitors like JAS239 warrants further investigation for GBM therapy.
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