MR imaging and spectroscopy reveals metabolic changes in glioblastoma driven by treatment with temozolomide and lonidamine

Resistance to temozolomide (TMZ) limits the efficacy of treatment in glioblastoma (GBM) and it is fuelled by a metabolic reprogramming of the cancer cells. Lonidamine (LND), a glycolytic and mitochondrial inhibitor, was used in combination with TMZ to evaluate metabolic and microstructural changes in a GBM model. C57BL/6 mice bearing intracranial GL261 tumours were treated with saline, LND, TMZ, or LND + TMZ for five consecutive days. In vivo longitudinal MRI included diffusion weighted imaging (DWI), and lactate-edited ¹H-MRS and the results were confirmed with immunohistochemistry for MCT4 expression. In vitro, acute and chronic bioenergetic reprogramming of GL261 cells was assessed. A significant decrease in lactate was observed in the LND and LND + TMZ groups indicating a change in their glycolytic flux. This metabolic shift was consistent with a marked reduction in MCT4 protein, the lactate transporter. In vitro bioenergetic profiling revealed an acute decrease in mitochondrial respiration, with partial recovery at later time points. Although a limited therapeutic benefit of addition LND to TMZ was observed, its tumour-selective activity and effect on tumour microenvironment seems promising and its long-term effects on tumour development should be investigated as part of an optimized combination strategy for TMZ treatment.