Metabolic MRI of paediatric-type diffuse high grade glioma and its response to therapy in vivo

Paediatric-type diffuse high grade glioma (PDHGG) is a leading cause of tumour-related death in children and young adults, and novel therapeutic approaches are urgently needed (1).

The increasing understanding of metabolic reprogramming in these tumours, associated with epigenetic modification in histone H3 mutant tumours, and alterations in other oncogenic signalling pathways, is revealing therapeutic vulnerabilities that could be targeted for improved treatment.

This project will use magnetic resonance imaging (MRI) approaches sensitive to tissue biochemistry to image dysregulated cancer metabolism in orthotopically propagated in vivo models of PDHGG. These methods will be used, alongside conventional MRI imaging, to provide early imaging biomarkers of tumour detection/delineation and response to therapeutic strategies affect tumour metabolism.

The metabolic MRI techniques established on our dedicated pre-clinical horizontal bore MRI scanner include:

i) Chemical exchange saturation transfer (CEST) MRI, which can provide information relating to immobile and mobile macromolecules, as well as proteins (2). Longitudinal CEST MRI data will be acquired to map and quantify the evolving metabolic phenotype across a panel of orthotopic PDHGG models that display different growth characteristics. CEST MRI will also be used to monitor PDHGG response to therapeutic strategies predicted to alter the macromolecular signature of tumours, e.g. radiotherapy, and to evaluate new interventions.

ii) Deuterium metabolic imaging (DMI), which is a MR spectroscopy technique that uses substrates labelled with deuterium (²H), a MR visible isotope of hydrogen, to inform on specific metabolic pathways. The metabolism of [²H]-glucose can be assessed dynamically as glycolysis results in detectable labelling of lactate, and the entry of labelled pyruvate into the TCA cycle leads to detectable glutamine/glutamate (3,4). This method will be used in PDHGG models, both in vitro and in vivo, to evaluate tumour response and resistance to molecularly targeted therapeutics predicted to alter glucose metabolism, such as PI3K/mTOR inhibitor paxalisib and MEK inhibitor trametinib.

Clinical translation of these methods will be explored via the London Collaborative Ultra-high field System (LoCUS) facility, a clinical 7T MRI system located within St. Thomas Hospital, for which the ICR is the lead oncology partner.

Candidates must have, or be on track to receive, a First- or Upper Second- class Honours degree (or a Masters) in Biological Sciences, Physics or Engineering and have a keen interest in pursuing paediatric brain tumour research.