Investigation of metabolism in glioblastoma patient-derived xenografts using deuterium metabolic imaging

The identification of metabolic subtypes of cancer could be used to indicate prognosis and sensitivity to treatment. Conventional anatomical imaging techniques provide morphological information, such as tumour size and perfusion. However, they do not provide any information on metabolic activity, which in treated tumours can precede anatomical changes. Position emission tomography (PET) is the only metabolic imaging technique that is currently routinely available in the clinic, however, it only provides information on substrate uptake and not downstream metabolism. In this project, deuterium metabolic imaging (DMI), in the form of 2H spectroscopy and 2H chemical shift imaging (CSI), was used to study glucose and acetate metabolism in patient-derived xenografts (PDX) of glioblastoma in mice and rats respectively. Using 2H-labelled glucose, I showed that despite exhibiting the same concentration of glucose within the tumour, glycolytic PDX subtypes produced more labelled lactate and mitochondrial PDX subtypes more labelled glutamine and glutamate pool (Glx). These metabolic subtypes also showed a differential metabolic response to chemoradiation, which was detectable before any anatomical changes were observed on conventional 1H magnetic resonance imaging (MRI). Targeting metabolism in the treatment of cancer has led to a number of promising novel metabolic inhibitors reaching the clinical trial phase of drug development. I showed that inhibiting mitochondrial complex 1 resulted in a reduction in tricarboxylic acid (TCA) cycle activity and a compensatory increase in glycolysis, and that the mitochondrial subtype is more sensitive to this treatment. Moreover, 2H CSI could be used to image these metabolic changes in vivo. Finally, I explored the potential of using 2H-labelled acetate to investigate fatty acid metabolism and the activity of the enzyme acetyl-CoA synthetase 2 (ACSS2) in vitro. Detecting downstream metabolites in vivo can be challenging due to their relatively low concentrations. Here, I showed that semi-heavy water (HDO) labelling from 2H-labelled acetate can be used as a surrogate marker of fatty acid synthesis.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Low, Jacob

Advisor dc:contributor.advisor

• Brindle, Kevin

• deuterium
• glioblastoma
• metabolic imaging
• spectroscopy

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/2a20e08a-0847-489d-a0ca-65bcaa667294/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.115233

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/379022