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.

Keywords

• animal model
• dynamic contrast-enhanced MRI
• pharmacokinetic models
• intra-tumoral heterogeneity
• glioblastoma
• clustering