Assessing Tumour Haemodynamic Heterogeneity and Response to Choline Kinase Inhibition Using Clustered Dynamic Contrast Enhanced MRI Parameters in Rodent Models of Glioblastoma

Abstract

To investigate the utility of DCE-MRI derived pharmacokinetic parameters in evaluating tumour haemodynamic heterogeneity and treatment response in rodent models of glioblastoma, imaging was performed on intracranial F98 and GL261 glioblastoma bearing rodents. Clustering of the DCE-MRI-based parametric maps (using Tofts, extended Tofts, shutter speed, two-compartment, and the second generation shutter speed models) was performed using a hierarchical clustering algorithm, resulting in areas with poor fit (reflecting necrosis), low, medium, and high valued pixels representing parameters , Ktrans , ve, Kep, vp, τi and Fp. There was a significant increase in the number of necrotic pixels with increasing tumour volume and a significant correlation between ve and tumour volume suggesting increased extracellular volume in larger tumours. In terms of therapeutic response in F98 rat GBMs, a sustained decrease in permeability and perfusion and a reduced cell density was observed during treatment with JAS239 based on Ktrans , Fp and ve as compared to control animals. No significant differences in these parameters were found for the GL261 tumour, indicating that this model may be less sensitive to JAS239 treatment regarding changes in vascular parameters. This study demonstrates that region-based clustered pharmacokinetic parameters derived from DCE-MRI may be useful in assessing tumour haemodynamic heterogeneity with the potential for assessing therapeutic response.

Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia

“…Whilst we previously demonstrated anti-tumour activity of JA239 in vivo ,[32] we here provide further understanding of its molecular mechanisms of action including the changes in intracellular metabolites and the cellular effects on proliferation and invasion. We noticed an important cell line to cell line variability, likely representative of the clinical heterogeneity of these tumours displaying a range of molecular subtypes and mutational burden.…”

“…[16] Additionally, in previous in vivo experiments we used 1 H NMR spectroscopy ( 1 H MRS) to assess JAS239 efficacy in three GBM xenograft rodent models (GL261, F98 and 9L) and demonstrated a reduction in total choline levels in all three models in response to JAS239, with the 9L intracranial tumours exhibiting the largest reduction. [32] Interestingly, the opposite trend was observed in tumour volume; when compared to baseline, the largest tumour growth arrest was found in GL261 and F98 tumours followed by 9L tumours. [32] These in vivo data support observations we have made in this study with respects to JAS239 induced reductions in proliferation via cell cycle arrest, with no effect on cell viability.…”

“…[32] Interestingly, the opposite trend was observed in tumour volume; when compared to baseline, the largest tumour growth arrest was found in GL261 and F98 tumours followed by 9L tumours. [32] These in vivo data support observations we have made in this study with respects to JAS239 induced reductions in proliferation via cell cycle arrest, with no effect on cell viability. The in vitro data obtained in this study, also explain why in vivo conditions, only a tumour growth arrest was observed, as opposed to a reduction in tumour volume [21].…”

“…[30,31] The efficacy of JAS239 treatment has also been demonstrated in in vivo rodent models of breast cancer and GBM. [16,32] The initial studies by Arlauckas et al, reported JAS239 efficacy with a significant reduction in total choline levels and tumour growth in a breast cancer xenograft model. [16] Additionally, in previous in vivo experiments we used 1 H NMR spectroscopy ( 1 H MRS) to assess JAS239 efficacy in three GBM xenograft rodent models (GL261, F98 and 9L) and demonstrated a reduction in total choline levels in all three models in response to JAS239, with the 9L intracranial tumours exhibiting the largest reduction.…”

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

“…Inhibition of ChoK has shown promising results in vivo across breast and GBM models via measurement of tCho, alterations of which are considered to be driven via changes in PC levels, using MRS 19,20 . In a recent study in F98 tumors, we reported a sustained decrease in permeability and perfusion and increased necrosis in response to the second‐generation ChoK inhibitor JAS239 39 . Our study investigated JAS239 treatment on GBM metabolism, and demonstrated a trend of reduction in tCho concentration and tCho/tCr ratio in all GBM models treated with JAS239.…”