Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

Sourav Bhaduri; Claire Louise Kelly; Clémentine Lesbats; Jack Sharkey; Lorenzo Ressel; Soham Mukherjee; Mark David Platt; Edward J Delikatny; Harish Poptani

doi:10.1002/nbm.4855

Metabolic changes in glioblastomas in response to choline kinase inhibition: In vivo MRS in rodent models

NMR Biomed. 2023 Mar;36(3):e4855. doi: 10.1002/nbm.4855. Epub 2022 Nov 10.

Authors

Sourav Bhaduri¹, Claire Louise Kelly¹, Clémentine Lesbats^{1

2}, Jack Sharkey¹, Lorenzo Ressel³, Soham Mukherjee¹, Mark David Platt¹, Edward J Delikatny⁴, Harish Poptani¹

Affiliations

¹ Centre for Preclinical Imaging, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
² Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
³ Department of Veterinary Anatomy Physiology and Pathology, University of Liverpool, Chester, UK.
⁴ Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.

Keywords: 1H MRS; JAS239; animal model; choline kinase; glioblastoma.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / drug therapy
Brain Neoplasms* / metabolism
Choline / metabolism
Choline Kinase
Glioblastoma* / diagnostic imaging
Glioblastoma* / drug therapy
Mice
Rats
Receptors, Antigen, T-Cell
Rodentia / metabolism

Substances

Choline Kinase
Receptors, Antigen, T-Cell
Choline